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Stephen B. McMahon, FMedSci, FSB Irene Tracey, MA (Oxon.), PhD, FRCA

Sherrington Professor of Physiology Nufeld Professor of Anaesthetic Science
Director, London Pain Consortium Director, Oxford Centre for Functional Magnetic Resonance
Academic Lead, Europain Imaging of the Brain
Wolfson Centre for Age-Related Diseases Head, Nufeld Division Anaesthetics
Kings College London Nufeld Department of Clinical Neurosciences
London, UK University of Oxford
Oxford, UK
Martin Koltzenburg, MD, FRCP
Professor of Clinical Neurophysiology Dennis C. Turk, PhD
UCL Institute of Neurology John and Emma Bonica Professor of Anesthesiology and
Co-Director, MRC Centre for Neuromuscular Diseases Pain Research
University College London Director, Center for Pain Research on Impact, Measurement,
Head of Department and Effectiveness (C-PRIME)
Department of Clinical Neurophysiology Department of Anesthesiology and Pain Medicine
The National Hospital for Neurology and Neurosurgery University of Washington
UCLH NHS Foundation Trust Seattle, Washington, USA
Queen Square, London, UK
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899


Copyright 2013 by Saunders, an imprint of Elsevier Ltd.
Copyright 1984, Longman Group Limited
Copyright 1989, 1994 Longman Group UK Limited
Copyright 1999, Harcourt Publishers Limited
Copyright 2006, Elsevier Limited.

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This book and the individual contributions contained in it are protected under copyright by the Publisher
(other than as may be noted herein).


Knowledge and best practice in this eld are constantly changing. As new research and experience
broaden our understanding, changes in research methods, professional practices, or medical treat-
ment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluat-
ing and using any information, methods, compounds, or experiments described herein. In using such
information or methods they should be mindful of their own safety and the safety of others, including
parties for whom they have a professional responsibility.
With respect to any drug or pharmaceutical products identied, readers are advised to check the
most current information provided (i) on procedures featured or (ii) by the manufacturer of each
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Library of Congress Cataloging-in-Publication Data

Wall and Melzacks textbook of pain / edited by Stephen B. McMahon ... [et al.]. -- 6th ed.
p. ; cm.
Textbook of pain
McMahons name appears rst on the 5th edition.
Includes bibliographical references and index.
ISBN 978-0-7020-4059-7 (hardcover : alk. paper)
I. McMahon, S. B. (Stephen B.) II. Title: Textbook of pain.
[DNLM: 1. Pain. 2. Pain Management--methods. WL 704]
616.0472--dc23 2012029999

Executive Content Strategist: Michael Houston

Manager, Content Development: Rebecca Gruliow
Publishing Services Manager: Patricia Tannian
Senior Project Manager: Sharon Corell
Design Direction: Steven Stave

Printed in the United States of America

Last digit is the print number 9 8 7 6 5 4 3 2 1

To Patrick Wall
teacher, colleague, and friend

Zahid Ali, PhD Inna Belfer, MD, PhD

Senior Director Associate Professor
Clinical Research Departments of Anesthesiology and Human Genetics
Pzer Neusentis Director
Cambridge, UK Molecular Epidemiology of Pain Program
University of Pittsburgh/UPMC
David A. Andersson, PhD Pittsburgh, Pennsylvania, USA
Lecturer in Physiology
Wolfson Centre for Age-Related Diseases Carlos Belmonte, MD, PhD
Kings College London Professor
London, UK Instituto de Neurociencias de Alicante
Universidad Miguel Hernandez-CSIC
A. Vania Apkarian, PhD Alicante, Spain
Department of Physiology David L.H. Bennett, MB, PhD
Northwestern University Reader in Pain Neurosciences
Feinberg School of Medicine The Nufeld Department of Clinical Neuroscience
Chicago, Illinois, USA The University of Oxford
Oxford, UK
Mark L. Baccei, PhD
Associate Professor Charles B. Berde, MD, PhD
Department of Anesthesiology Chief
University of Cincinnati Division of Pain Medicine
Cincinnati, Ohio, USA Department of Anesthesiology, Perioperative and Pain Medicine
Boston Childrens Hospital
Miroslav (Misha) Bakonja, MD Professor of Anesthesia and Pediatrics
Medical Director of Neuroscience Harvard Medical School
CRILifeTree Clinical Research Boston, Massachusetts, USA
Salt Lake City, Utah
Emeritus Professor Odd-Geir Berge, DDS, PhD
Department of Neurology Adjunct Professor
University of Wisconsin Department of Surgical Sciences, Uppsala
Madison, Wisconsin, USA Uppsala Berzelii Center
Uppsala, Sweden
Ralf Baron, MD
Professor Stuart Bevan, PhD
Chair of the Division of Neurological Pain Research Professor of Pharmacology
and Therapy Wolfson Centre for Age-Related Diseases
Department of Neurology Kings College London
University Hospital Schleswig-Holstein London, UK
Kiel, Germany
Klaus Bielefeldt, MD, PhD
Simon Beggs, PhD Associate Professor of Medicine
Research Associate Division of Gastroenterology
Assistant Professor University of Pittsburgh Medical Center
Program in Neurosciences and Mental Health Pittsburgh, Pennsylvania, USA
Hospital for Sick Children, Toronto
Faculty of Dentistry Andreas Binder, MD
University of Toronto Consultant
Toronto, Ontario, Canada Division of Neurological Pain Research and Therapy
Department of Neurology
University Clinic Schleswig-Holstein
Kiel, Germany

Harald Breivik, MD, DMedSci A.D. (Bud) Craig, PhD

Professor Atkinson Research Scientist
University of Oslo Barrow Neurological Institute
Consultant Phoenix, Arizona
Department of Pain Management and Research Research Professor
Oslo University Hospital, Rikshospitalet Cell Biology and Anatomy
Oslo, Norway University of Arizona College of Medicine
Tucson, Arizona
Kay Brune, MD, PhD Research Professor
Doerenkamp Professor Department of Psychology
Department of Experimental and Clinical Pharmacology Arizona State University
and Toxicology Tempe, Arizona, USA
Friedrich-Alexander University Erlangen-Nuremberg
Erlangen, Germany John B. Davis, PhD
Biology Head
M. Catherine Bushnell, PhD Convergence Pharmaceuticals Ltd.
Harold Grifth Professor Cambridge, UK
Department of Anesthesia
McGill University John M. Dawes, PhD
Montreal, Quebec, Canada Wolfson Centre for Age-Related Diseases
Kings College London
Asokumar Buvanendran, MD London, UK
Director of Orthopedic Anesthesia
Professor of Anesthesiology Marshall Devor, PhD
Rush University Medical Center Department of Cell and Developmental Biology
Chicago, Illinois, USA Institute of Life Sciences and the Center for Research on Pain
The Hebrew University of Jerusalem
James N. Campbell, MD Jerusalem, Israel
Professor Emeritus
Department of Neurosurgery Anthony Dickenson, BSc, PhD
The Johns Hopkins University Professor of Neuropharmacology
CEO Neuroscience, Physiology, and Pharmacology
Arcion Therapeutics University College London
Baltimore, Maryland, USA London, UK

H. Isaac Chen, MD Andrew Dickman, DPharm, MSc

Resident Consultant Pharmacist
Department of Neurosurgery Department of Palliative Care
Hospital of the University of Pennsylvania Blackpool Teaching Hospitals NHS Foundation Trust
Philadelphia, Pennsylvania, USA Blackpool, UK
Consultant Pharmacist
Nathan I. Cherny, MBBS, FRACP, FRCP Marie Curie Palliative Care Institute Liverpool (MCPCIL)
Norman Levan Chair of Humanistic Medicine University of Liverpool
Cancer Pain and Palliative Medicine Service Liverpool, UK
Shaare Zedek Medical Center
Jerusalem, Israel Andrew Dilley, PhD
Lecturer in Anatomy
John J. Collins, MBBS, PhD, FAChPM, FFPMANZCA, Division of Clinical and Laboratory Investigation
FRACP Brighton and Sussex Medical School
Head of Department University of Sussex
Pain Medicine and Palliative Care Falmer, Brighton, UK
The Childrens Hospital at Westmead
Clinical Associate Professor Ray J. Dolan, MD
Discipline of Paediatrics and Child Health Mary Kinross Professor of Neuropsychiatry
University of Sydney Wellcome Trust Centre for Neuroimaging
Sydney, New South Wales, Australia University College London
London, UK

Michael J. Dorsi, MD
Ventura County Neurosurgical Associates
Community Memorial Hospital
Ventura, California, USA

Jonathan O. Dostrovsky, BSc, MSc, PhD Herta Flor, PhD

Professor Emeritus Scientic Director
Department of Physiology Department of Cognitive and Clinical Neuroscience
Faculty of Medicine Central Institute of Mental Health and University of
Department of Oral Physiology Heidelberg, Mannheim
Faculty of Dentistry Mannheim, Germany
University of Toronto
Toronto, Ontario, Canada Karen Forbes, MBChB, EdD
Professorial Teaching Fellow
John E. Ellershaw, MBBCh, MA, FRCP University of Bristol
Professor of Palliative Medicine Honorary Consultant in Palliative Medicine
Marie Curie Palliative Care Institute Liverpool (MCPCIL) Department of Palliative Medicine
University of Liverpool University Hospitals Bristol NHS Foundation Trust
Liverpool, UK Bristol, UK

Edzard Ernst, MD, PhD, FMedSci, FSB, FRCP, FRCPEd Lucia Gagliese, PhD
Professor Associate Professor
Department of Complementary Medicine School of Kinesiology and Health Science
Peninsula Medical School, University of Exeter York University
Exeter, Devon, UK Senior Scientist
Ontario Cancer Institute
David Felson, MD, MPH University Health Network
Professor of Medicine and Epidemiology Scientist
Department of Medicine Department of Anesthesia and Pain Management
Boston University School of Medicine University Health Network
Boston, Massachusetts, USA Toronto, Ontario, Canada

Howard L. Fields, MD, PhD Gerald F. Gebhart, PhD

Professor Director, Center for Pain Research
Department of Neurology Department of Anesthesiology
University of California, San Francisco University of Pittsburgh
San Francisco, California, USA Pittsburgh, Pennsylvania, USA

Nanna Brix Finnerup, MD, DrMedSc Jennifer L. Gibbs, MAS, DDS, PhD
Associate Professor Assistant Professor
Danish Pain Research Center Department of Endodontics
Aarhus University New York University
Aarhus, Denmark New York, New York, USA

David A. Fishbain, BSC (Hon), MSC, MD, Ian Gilron, MD, MSc, FRCPC
Distinguished FAPA Director of Clinical Pain Research
Professor Department of Anesthesiology & Perioperative Medicine
Department of Psychiatry Queens University
Miller School of Medicine Professor, Departments of Anesthesiology & Perioperative
University of Miami Medicine and Biomedical & Molecular Sciences
Adjunct Professor Queens University
Departments of Neurological Surgery and Anesthesiology Kingston, Ontario, Canada
Miller School of Medicine
Professor Peter J. Goadsby, MD, PhD, DSc
Research Professor
Rosomoff Pain Center Headache GroupDepartment of Neurology
Miami, Florida, USA University of California, San Francisco
San Francisco, California, USA
Maria Fitzgerald, BA, PhD, FMedSci
Professor of Developmental Neurobiology Michael S. Gold, PhD
Department of Neuroscience, Physiology, and Pharmacology Professor
University College London Department of Anesthesiology
London, UK University of Pittsburgh
Pittsburgh, Pennsylvania, USA

Veeraindar Goli, MD, MBA, DFAPA Kenneth M. Hargreaves, DDS, PhD

Vice President, Clinical Disease Area ExpertPain Professor
Primary Care Clinical Sciences Departments of Endodontics, Pharmacology, Physiology,
Pzer, Inc. and Surgery
Cary, North Carolina University of Texas Health Science Center at San Antonio
Emeritus Professor San Antonio, Texas, USA
Duke University Medical Center
Durham, North Carolina, USA Jennifer A. Haythornthwaite, PhD
Allan Gottschalk, MD, PhD Department of Psychiatry and Behavioral Sciences
Associate Professor The Johns Hopkins University School of Medicine
Department of Anesthesiology and Critical Care Medicine Baltimore, Maryland, USA
The Johns Hopkins University
Baltimore, Maryland, USA Mary M. Heinricher, PhD
Richard H. Gracely, PhD Departments of Neurological Surgery and Behavioral
Professor Neuroscience
Regional Center for Neurosensory Disorders Oregon Health and Science University
University of North Carolina Portland, Oregon, USA
Chapel Hill, North Carolina
Adjunct Professor Raymond G. Hill, BPharm, PhD, DSc (Hon), FMedSci
Department of Internal MedicineRheumatology Visiting Professor of Pharmacology
University of Michigan Department of Medicine
Ann Arbor, Michigan, USA Imperial College London
London, UK
Jane Greening, PhD, MSc, MCSP
Hon. Senior Research Fellow Andrea G. Hohmann, PhD
Division of Clinical and Laboratory Investigation Linda and Jack Gill Chair of Neuroscience and Professor
Brighton and Sussex Medical School Department of Psychological & Brain Sciences
University of Sussex Indiana University
Falmer, Brighton, UK Bloomington, Indiana, USA

Joel D. Greenspan, PhD Tomas G.M. Hkfelt, PhD, MD

Professor and Chair Professor of Histology and Cell Biology
Department of Neural and Pain Sciences Department of Neuroscience
University of Maryland School of Dentistry Karolinska Institutet
Professor Stockholm, Sweden
Program in Neuroscience
University of Maryland Peter Hoskin, MD, FRCP, FRCR
Baltimore, Maryland, USA Consultant in Clinical Oncology
Cancer Centre
Arpana Gupta, PhD Mount Vernon Hospital
Postdoctoral Research Fellow Northwood, UK
Oppenheimer Family Center for Neurobiology of Stress Professor in Clinical Oncology
Semel Institute of Neuroscience and Human Behavior University College London
Department of Psychiatry and Biobehavioral Sciences London, UK
David Geffen School of Medicine
University of California, Los Angeles Stephen P. Hunt, BSc, PhD
Los Angeles, California, USA Professor of Molecular Neuroscience
Department of Cell and Developmental Biology
Hermann O. Handwerker, MD University College London
Professor London, UK
Department of Experimental and Clinical Pharmacology
and Toxicology Smriti Iyengar, PhD
Friedrich-Alexander Senior Research Scientist
University Erlangen-Nuremberg Eli Lilly and Company
Erlangen, Germany Indianapolis, Indiana, USA

Wilfrid Jnig, MD
Department of Physiology
Christian-Albrechts University Kiel
Kiel, Germany

Troels Staehelin Jensen, MD, DMSc Promil Kukreja, MD, PhD

Professor Assistant Professor
Department of Neurology and Danish Pain Research Center Department of Anesthesiology
Aarhus University Hospital Medical Director
Aarhus, Denmark Regional Anesthesia Pain Service
University of Alabama at Birmingham
Gareth T. Jones, BSc (Hon), MScEcon, PhD Birmingham, Alabama, USA
Senior Lecturer in Epidemiology
Aberdeen Pain Research Collaboration (Epidemiology John Y.K. Lee, MD
Group) Assistant Professor
School of Medicine and Dentistry Department of Neurosurgery
University of Aberdeen University of Pennsylvania
Aberdeen, UK Philadelphia, Pennsylvania, USA

Joel Katz, PhD Fred A. Lenz, MD, PhD, FRCS(C)

Professor and Canada Research Chair in Health Psychology A. Earl Walker Professor
Department of Psychology Department of Neurosurgery
York University The Johns Hopkins Hospital
Professor Baltimore, Maryland, USA
Department of Anesthesia
University of Toronto Jon D. Levine, MD, PhD
Director, Acute Pain Research Unit Professor
Department of Anesthesia and Pain Management Department of Medicine
Toronto General Hospital University of California, San Francisco
Toronto, Ontario, Canada San Francisco, California, USA

Brigitte L. Kieffer, PhD Bengt Linderoth, MD, PhD

Translational Medicine and Neurogenetics Professor
Institut de Gntique et de Biologie Molculaire et Cellulaire Department of Clinical Neuroscience
Illkirch, France Section of Neurosurgery
Karolinska Institutet/Karol University Hospital
H. Richard Koerber, PhD Stockholm, Sweden
Department of Neurobiology Arthur G. Lipman, PharmD, FASHP
University of Pittsburgh, School of Medicine University Professor
Pittsburgh, Pennsylvania, USA Department of Pharmacotherapy
College of Pharmacy
Bart Koes, MSc, PhD Adjunct Professor
Professor Department of Anesthesiology
Department of General Practice School of Medicine
Erasmus MC Director of Clinical Pharmacology
Rotterdam, The Netherlands Pain Management Center
University Healthcare
Martin Koltzenburg, MD, FRCP University of Utah Health Sciences Center
Professor of Clinical Neurophysiology Salt Lake City, Utah, USA
UCL Institute of Neurology
Co-Director, MRC Centre for Neuromuscular Diseases Richard Lipton, MD
University College London Edwin S. Lowe Professor
Head of Department Vice Chair of Neurology
Department of Clinical Neurophysiology Professor of Epidemiology and Population Health
The National Hospital for Neurology and Neurosurgery Professor of Psychiatry and Behavioral Sciences
UCLH NHS Foundation Trust Albert Einstein College of Medicine
Queen Square, London, UK Bronx, New York, USA

Jeffrey S. Kroin, PhD Donlin M. Long, MD, PhD

Professor Distinguished Professor of Neurosurgery
Department of Anesthesiology Johns Hopkins Medical Institute
Rush Medical College Baltimore, Maryland, USA
Chicago, Illinois, USA

Timothy R. Lubenow, MD Henry J. McQuay, DM, FRCA, FRCP

Professor Emeritus Fellow
Department of Anesthesiology Balliol College
Rush University Medical Center Oxford, Oxon, UK
Chicago, Illinois, USA
Ronald Melzack, PhD
Gary J. Macfarlane, BSc (Hon), MBChB, PhD, Professor Emeritus
CStat, MD (Hon) Department of Psychology
Professor of Epidemiology McGill University
Aberdeen Pain Research Collaboration (Epidemiology Group) Montreal, Quebec, Canada
School of Medicine and Dentistry
University of Aberdeen Siegfried Mense, MD
Aberdeen, UK Professor
Department of Neuroanatomy/Neurophysiology
Patrick W. Mantyh, PhD, JD Heidelberg University, Medical Faculty Mannheim,
Professor Mannheim, Germany
Department of Pharmacology
University of Arizona College of Medicine Richard A. Meyer, BSEE, MS
Tucson, Arizona, USA Professor Emeritus
Department of Neurosurgery
Mitchell B. Max, MD The Johns Hopkins University School of Medicine
Departments of Anesthesiology and Human Genetics Baltimore, Maryland, USA
University of Pittsburgh
Pittsburgh, Pennsylvania, USA Bjrn A. Meyerson, MD, PhD
Professor Emeritus
Emeran A. Mayer, MD Department of Clinical Neuroscience
Professor Karolinska Institutet
Department of Medicine, Physiology, and Psychiatry Stockholm, Sweden
Division of Digestive Diseases
University of California at Los Angeles Jeffrey S. Mogil, PhD
Director E.P. Taylor Professor of Pain Studies
Oppenheimer Family Center for Neurobiology of Stress Department of Psychology and Alan Edwards Centre for
University of California at Los Angeles Research on Pain
Los Angeles, California, USA McGill University
Montreal, Quebec, Canada
John McBeth, MA, PhD Professor
Reader Department of Anesthesiology and Human Genetics
Arthritis Research UK Primary Care Centre University of Pittsburgh
Keele University Pittsburgh, Pennsylvania, USA
Keele, UK
Honorary Reader Andrew Moore, MA, DPhil, CChem, FRSC, FRCA, DSc
Arthritis Research UK Epidemiology Unit Nufeld Division of Anaesthesia
University of Manchester Nufeld Department of Clinical Neuroscience
Manchester, UK University of Oxford
Oxford, UK
Patrick J. McGrath, OC, PhD, FRSC, FCAHS
Professor Valerie Morisset, PhD
Department of Psychology, Pediatrics, Psychiatry Head of Electrophysiology
Dalhousie Convergence Pharmaceuticals Ltd.
Vice President Cambridge, UK
Research and Innovation
IWK Health Centre and Capital District Health Authority Tuhina Neogi, MD, PhD, FRCPC
Halifax, Nova Scotia, Canada Associate Professor of Medicine
Clinical Epidemiology Research and Training Unit,
Stephen B. McMahon, FMedSci, FSB and Rheumatology
Sherrington Professor of Physiology Boston University School of Medicine
Director, London Pain Consortium Associate Professor
Academic Lead, Europain Department of Epidemiology
Wolfson Centre for Age-Related Diseases Boston University School of Public Health
Kings College London Boston, Massachusetts, USA
London, UK

Timothy J. Ness, MD, PhD Donald D. Price, PhD

Simon Gelman Professor Professor Emeritus
Department of Anesthesiology Department of Oral and Maxillofacial Surgery
University of Alabama at Birmingham University of Florida
Birmingham, Alabama, USA Gainesville, Florida, USA

Lone Nikolajsen, MD, PhD, DMSc Pierre Rainville, PhD

Clinical Associate Professor Professor
Department of Anesthesiology Department of Stomatology
Danish Pain Research Center Universit de Montral
Aarhus University Hospital Director
Aarhus, Denmark Laboratoire de recherche en neuropsychologie de la douleur
Centre de recherche de linstitut universitaire de griatrie de
Rodrigo Noseda, DVM, PhD Montral
Instructor in Anesthesia Montreal, Qubec, Canada
Department of Anesthesia, Critical Care,
and Pain Medicine Srinivasa N. Raja, MD
Beth Israel Deaconess Medical Center Professor
Harvard Medical School Department of Anesthesiology and Critical Care Medicine
Boston, Massachusetts, USA Professor
Department of Neurology
E. Andrew Ochroch, MD, MSCE Director
Associate Professor Division of Pain Medicine
Department of Anesthesiology, Critical Care, The Johns Hopkins University
and Surgery Baltimore, Maryland, USA
University of Pennsylvania
Philadelphia, Pennsylvania, USA Andrew S.C. Rice, MBBS, MD, FRCA, FFPMRCA
Professor of Pain Research
Michael H. Ossipov, PhD Department of Surgery and Cancer
Research Professor Imperial College
Department of Pharmacology Hon. Consultant in Pain Medicine
University of Arizona College of Medicine Chelsea and Westminster Hospital NHS Foundation Trust
Tucson, Arizona, USA London, UK

Joanne E. Palmer, BSc (Hon), MSc, PhD Matthias Ringkamp, MD

Head of Clinical Operations Associate Professor
Convergence Pharmaceuticals Ltd. Department of Neurosurgery
Cambridge, UK The Johns Hopkins University
Baltimore, Maryland, USA
Peter H. Pan, MSEE, MD
Professor and Director of Clinical Research I. Jon Russell, MS, MD, PhD, ACR Master
Section of Obstetric and Gynecologic Anesthesia Director
Department of Anesthesiology Fibromyalgia Research and Consulting
Wake Forest School of Medicine Arthritis and Osteoporosis Center of South Texas
Winston-Salem, North Carolina, USA Retired Faculty
University of Texas Health Science Center at San Antonio
Bruce G. Pollock, MD, PhD, FRCPC San Antonio, Texas, USA
Professor and Director
Division of Geriatric Psychiatry Michael W. Salter, MD, PhD
University of Toronto Associate Chief
Vice President, Research Science Strategy
Centre for Addiction and Mental Health Neurosciences & Mental Health Program
Toronto, Ontario, Canada Hospital for Sick Children
Frank Porreca, PhD Department of Physiology
Professor University of Toronto Centre for the Study of Pain
Department of Pharmacology University of Toronto
University of Arizona College of Medicine Toronto, Ontario, Canada
Tucson, Arizona, USA

Jrgen Sandkhler, MD, PhD Philip J. Siddall, MBBS, MM (Pain Mgt), PhD, FFPMANZCA
Director Associate Professor
Center for Brain Research Department of Pain Management
Medical University of Vienna Greenwich Hospital
Vienna, Austria HammondCare
University of Sydney
Simona Liliana Sava, MD Sydney, New South Wales, Australia
Headache Research Unit
University Department of Neurology Citadelle Hospital Maree T. Smith, BPharm (Hon), PhD
University of Lige Director, Centre for Integrated Preclinical Drug
Lige, Belgium Development
Professor of Pharmacy
John W. Scadding, MD, FRCP The University of Queensland
Honorary Consultant Neurologist Brisbane, Queensland, Australia
The National Hospital for Neurology and Neurosurgery
London, UK Linda S. Sorkin, PhD
Hans-Georg Schaible, MD Department of Anesthesiology
Director University of California, San Diego
Institute of Physiology 1/Neurophysiology La Jolla, California, USA
Jena University HospitalFriedrich Schiller University Jena
Jena, Germany Simon N. Tate, BSc
Chief Scientic Ofcer
Martin Schmelz, MD, PhD Convergence Pharmaceuticals Ltd.
Karl Feuerstein Professorship Cambridge, UK
Department of Anesthesiology
Heidelberg University Timo T. Tervo, MD, PhD
Mannheim, Germany Department of Ophthalmology
University of Helsinki
Jean Schoenen, MD, PhD Chief Physician
Professor Helsinki University Central Hospital
Department of Neurology Helsinki, Finland
Headache Research Unit
University of Lige Mick Thacker, PhD
Lige, Belgium Lecturer
Biomedical Sciences
Stephan A. Schug, MD, FANZCA, FFPMANZCA Centre of Human and Aerospace Physiological Sciences
Professor and Chair of Anaesthesiology Kings College London
Pharmacology and Anaesthesiology Unit London, UK
University of Western Australia
Director of Pain Medicine Andrew J. Todd, MBBS, PhD
Department of Anaesthesia and Pain Medicine Professor
Royal Perth Hospital Institute of Neuroscience and Psychology
Perth WA, Australia University of Glasgow
Glasgow, UK
Petra Schweinhardt, MD, PhD
Assistant Professor Thomas R. Toelle, MD, PhD
Alan Edwards Center for Research on Pain Professor
McGill University Department of Neurology
Montreal, Quebec, Canada Technische Universitt Mnchen
Mnchen, Germany
Ben Seymour, MBChB, MRCP, PhD
Principal Investigator Richard J. Traub, PhD
Center for Information and Neural Networks Professor
National Institute of Communications Technology Department of Neural and Pain Sciences
Japan University of Maryland School of Dentistry
Wellcome Clinical Fellow Baltimore, Maryland, USA
Computational and Biological Learning Lab
Department of Engineering
University of Cambridge
Consultant Neurologist
Addenbrookes Hospital
Cambridge, UK

Dennis C. Turk, PhD Heng Yu Wong, MD

John and Emma Bonica Professor of Anesthesiology and Director
Pain Research HY Wong Gastrointestinal and Liver Specialist Clinic
Director, Center for Pain Research on Impact, Measurement, Mount Elizabeth Medical Center
and Effectiveness (C-PRIME) Singapore
Department of Anesthesiology and Pain Medicine
University of Washington Paul J. Wrigley, MBBS, MM, PhD, FANZCA, FFPMANZCA
Seattle, Washington, USA Senior Lecturer
Pain Management Research Institute and Kolling Institute
Anita M. Unruh, PhD, MSW, OT(c), Reg NS of Medical Research
Associate Dean (Research & Academic) University of Sydney
Faculty of Health Professions Pain Medicine Senior Staff Specialist
Dalhousie University Pain Management Research Centre
Halifax, Nova Scotia, Canada Royal North Shore Hospital
Sydney, New South Wales, Australia
Catherine E. Urch, MRCP, PhD
Palliative Medicine Consultant Xiao-Jun Xu, PhD
Honorary Senior Lecturer Associate Professor
Imperial College Healthcare NHS Trust Department of Physiology and Pharmacology
Department of Palliative Care Section of Integrative Pain Research
Charing Cross Hospital Karolinska Institutet
London, UK Stockholm, Sweden

Maurits van Tulder, PhD Tony L. Yaksh, PhD

Professor Professor and Vice Chair for Research
Department of Health Sciences Department of Anesthesiology
Faculty of Earth and Life Sciences Professor
VU University Department of Pharmacology
Amsterdam, The Netherlands University of California, San Diego
La Jolla, California, USA
Marcelo Villar, MD, PhD
Professor Joanna Maria Zakrzewska, MD, FDSRCS, FFDRCSI,
Department of Neuroscience FFPMRCA, FHEA
Austral University Professor
Buenos Aires, Argentina Head of Facial Pain Unit
Division of Diagnostic, Surgical and Medical Sciences
Luis Villanueva, DDS, PhD Eastman Dental Hospital
Director of Research UCLH NHS Foundation Trust
CNRS London, UK
Pain Group Hanns Ulrich Zeilhofer, MD
INSERM Professor
Centre de Psychiatrie et Neurosciences Institute of Pharmacology and Toxicology
Paris, France University of Zurich
Tor D. Wager, PhD Institute of Pharmaceutical Sciences
Associate Professor ETH Zurich
Department of Psychology and Neuroscience Zurich, Switzerland
University of Colorado, Boulder
Boulder, Colorado, USA Xu Zhang, PhD
C. Peter N. Watson, MD, FRCPC Institute of Neuroscience
Assistant Professor Shanghai Institutes for Biological Sciences, Chinese Academy
Department of Medicine of Sciences
Division of Neurology Shanghai, China
University of Toronto
Toronto, Ontario, Canada

Zsuzsanna Wiesenfeld-Hallin, PhD

Professor and Head of Section of Integrative Pain Research
Department of Physiology and Pharmacology
Karolinska Institutet
Stockholm, Sweden

The gate control theory of pain, which Patrick Wall and I mechanisms that underlie acute and chronic pain. We are all
published in 1965, led to an explosion of research on pain very grateful to Michael Houston, Elseviers outstanding pub-
mechanisms in the spinal cord and brain and provided the lishing manager who ensured the timely publication of this
rationale for a variety of new approaches to pain therapy. In up-to-date edition. I am delighted with it and I know that
1984 we decided to edit a book with the latest information in Patrick, who died on August 8, 2001, would be equally pleased.
the rapidly growing eld so that clinicians could read about the Wall and I always aimed to achieve the broadest coverage
status of laboratory and clinical research and scientists could of the eld of pain in order to promote the ght against pain
learn about major clinical advances in the ght against pain. and suffering from every possible angle. Stephen McMahon,
The rst edition of the Textbook of Pain in 1984 was sold Dennis Turk, Irene Tracey, and Martin Koltzenburg have
out in a year. It was followed by new editions that tracked the maintained this goal by producing this outstanding new edi-
remarkable advances in the eld of pain research and therapy. tion. It is up to date and comprises a whole, unied body of
Shortly after publication of the fourth edition in 1999, Patrick knowledge that touches on every aspect of pain. The torch
Wall became ill. Our discussions about the Textbook of Pain has been handed to an exciting new generation of editors and
now centered on the need to maintain a balance in presenting contributors. Painparticularly chronic paincontinues to
the two facets of the eld of painresearch and therapy. That destroy the lives of millions of people worldwide. There is
goal was achieved in 2006 by Stephen McMahon and Martin no nobler goal than achieving the relief of pain and suffering.
Koltzenburg in the fth edition. This new edition will bring that day closer.
The scope of this sixth edition of the Textbook of Pain has
been expanded by the addition of two new editorsDennis Ronald Melzack
Turk and Irene Traceywho have made outstanding con- Professor Emeritus, McGill University
tributions to our understanding of the behavioral and brain Montreal, Canada

Patrick Wall (left) and Ronald Melzack. Ronald Melzack (left) and Patrick Wall.


The last edition of Wall and Melzacks Textbook of Pain merged others. The increasing body of literature also places
the fth editionwas published in 2006. There has been a burdens on the editors. For that reason I am tremendously
considerable increase in our understanding of the nature and grateful that Irene Tracey and Dennis Turk have joined the
mechanisms of pain since that date. This is reected in the editorial team and applied their distinct expertise to rening
enormous amount of published literature on pain. PubMed this textbook.
nds more than 160,000 publications since the last edition Despite advancing knowledge in the eld, the burden of
was published, using the search term pain. This repre- pain remains unacceptably high. Epidemiological studies,
sents about a 40% increase in publications compared with many reviewed in this book, point to the high prevalence
an equivalent period before publication of the fth edition. of chronic pain across the world associated with staggering
Bibliometric data also shows how some topics within the pain socioeconomic costs. Unfortunately, existing therapies fail to
eld have become a greater focus of attention than others. For offer good (let alone complete) pain relief to the majority of
instance, a search for the phrase neuropathic pain shows a these sufferers. There have been some modest advances with
nearly 90% increase in publication numbers since publication the approval of some new therapies, such as topical capsaicin
of the last edition of this textbook. Headache, by contrast, patches in some countries. A step chance in analgesic drug
shows a more modest increase, amounting to less than 30%. efcacy seems possible, too, as evidenced by the dramatic pain
Technology has allowed some topics to be explored by greater relief offered by blockers of NGF in a series of clinical trials
numbers of researchers. The falling cost of DNA and RNA also reviewed in this book. We are still waiting to nd out if
sequencing and associated technologies is likely to have con- side effects will limit or block this initiative. But the example
tributed to some of the 60% increase in publications found serves to illustrate that a good understanding of pain and pain
with the search terms genetics and pain. Between the mechanisms can lead to effective therapies.
beginning of 2001 and the end of 2006, PubMed nds but This is a difcult time for pharmaceutical companies, who
a single publication with the search terms epigenetics and have struggled with the many problems associated with trans-
pain. Since then, 19 papers have emerged, and one suspects lating new knowledge into new therapies in this area and
this will be the beginning of a new ood of interest. many others. We hope that this new edition of Wall and Mel-
The current edition of Wall and Melzacks Textbook of zacks Textbook of Pain will help all those interested in this
Pain, the sixth, tries to capture and report on the most impor- eldacademic scientists, clinicians, and industry leadersto
tant developments in the eld over the last 6 years. Collec- do their work more effectively. We sincerely hope they suc-
tively, the 147 authors who contribute to the current edition ceed in their efforts to bring about a positive change for
have probably read a large proportion of those 160,000 new another group of stakeholders herethe sufferers of pain.
publications. In this new edition we have retained the same
general structure that we created for the fth edition, but we Stephen B. McMahon, FMedSci, FSB
have added some chapters to reect new developments and London

Abbreviations and Acronyms

ABC ATP-binding cassette BKN bradykinin

AC adenylate cyclase BMD bone mineral density
ACC anterior cingulate cortex BMI body mass index
ACG anterior cingulate gyrus BMS burning mouth syndrome
ACh acetylcholine BOCF baseline observation carried forward
ACL anterior cruciate ligament BOLD blood oxygenation leveldependent
ACOG American College of Obstetricians and BPI Brief Pain Inventory
Gynecologists BPS bladder pain syndrome
ACPA anticyclic citrulated peptide antibody BTcP breakthrough cancer pain
ACR American College of Rheumatology CABG coronary artery bypass grafting
ACTH adrenocorticotropic hormone CAIEB clinician-administered intermittent bolus
ADAPT Arthritis Diet and Activity Promotion Trial CAM complementary and alternative medicine;
ADEPT attitude, diagnosis, education, physical constitutively activated mutant
treatment, living CAMKII calciumcalmodulindependent kinase II
ADP adenosine diphosphate protein
AEA arachidonyl ethanol amide CASPAR2 contactin-associated protein 2
AED antiepileptic drug CAV cyclophosphamide, Adriamycin (doxorubicin),
2-AFC two alternative forced choice (method) and vincristine
AFP atypical facial pain CBF cerebral blood ow
2-AG 2-acylglycerol; 2-arachidonoylglycerase CBT cognitivebehavioral therapy
AIA antigen-induced monarthritis CCI chronic constriction injury (model)
AIM ancestry informative marker CCK cholecystokinin
AIP acute inammatory polyneuropathy CDH chronic daily headache
AMH A-ber mechano-heatsensitive nociceptor; A CEI continuous epidural infusion
bers responsive to mechanical and heat stimuli CEP cortical evoked potential
AMI acute myocardial infarction CER control event rate
AMP adenosine monophosphate CES-D Center for Epidemiological StudiesDepression
AMPA -amino-3-hydroxy-5-methyl-4- Scale
isoxazolepropionic acid CFA complete Freunds adjuvant
ANS autonomic nervous system CFACS Child Facial Action Coding System
AO atypical odontalgia CFS chronic fatigue syndrome
AP action potential cGMP cyclic guanosine monophosphate
APF antiproliferative factor CGRP calcitonin generelated peptide
APM Association for Palliative Medicine of Great CH cluster headache
Britain and Ireland CHEOPS Childrens Hospital of Eastern Ontario Pain
APML acute promyelocytic leukemia Scale
APSF Anesthesia Patient Safety Foundation CHEP contact heatevoked potential
AS anxiety sensitivity CI condence interval
ASA American Society of Anesthesiologists CIA collagen-induced polyarthritis
ASIC acid-sensing ion channel CIBP cancer-induced bone pain
ATF3 activated transcription factor 3 CIDP chronic inammatory demyelinating
ATL aspirin-triggered lipoxin polyneuropathy
ATP adenosine triphosphate CIPA congenital insensitivity to pain with anhidrosis
AU action unit CISS constructive interference steady state (MRI)
AUA American Urological Society CL centralateral
AVM arteriovenous malformation CLASS Celecoxib Long-term Arthritis Safety Study
BBB bloodbrain barrier CMH C-ber mechanoheatsensitive nociceptors
BCG bacille Calmette-Gurin CMM conventional medical management
BDI Beck Depression Inventory CMT CharcotMarieTooth (disease)
BDNF brain-derived neurotrophic factor CNCP chronic non-cancer pain
BH4 tetrahydrobiopterin CNS central nervous system
bHLH basic helixloophelix COMT catechol O-methyltransferase


CONSORT Consolidated Standards of Reporting Trials d4t stavudine

Cox, COX cyclooxygenase DTI diffusion tensor imaging
CP chronic prostatitis DVT deep vein thrombosis
CPCI Chronic Pain Coping Inventory DZ dizygotic
CPM conditional pain modulation EAACI excitatory amino acid carrier 1
CPP chronic pain patient; chronic pelvic pain; EC epidural compression
conditioned place preference EDTMP ethylene diamine tetramethylene phosphonate
CPPS chronic pelvic pain syndrome EEG electroencephalogram
CPR cardiopulmonary resuscitation EER experimental event rate
CPSP central poststroke pain EERW enrolled enrichment with randomized
CR conditional response withdrawal
CREB cyclic AMP response elementbinding protein EET epoxyeicosatrienoic acid
CRF corticotropin-releasing factor EGF epidermal growth factor
CRH corticotropin-releasing hormone eGFR estimated GFR
CRHCS complexity regarding the health care system EII embryonic day II
CRPS complex regional pain syndrome EM extensive metabolizer
CS conditioned stimulus EMDR eye movement desensitization and reprocessing
CSCI continuous subcutaneous infusion EMEA European Medicines Evaluation Agency
CSD cortical spreading depression EMG electromyography
CSE combined spinal epidural (technique) ENaC epithelial Na+ channel
CSF cerebrospinal uid; colony-stimulating factor ENF epidermal nerve ber
CSQ Coping Strategies Questionnaire eNOS endothelial nitric oxide synthase
CSS CRPS severity score EP etoposide and cisplatin
CT computed tomography EPH episodic paroxysmal hemicrania
CTB cholera toxin B EPSC excitatory post-synaptic current
CTS carpal tunnel syndrome EPSP excitatory post-synaptic potential
CTTH chronic tension-type headache EQ European Quality of Life instrument
CWP chronic widespread pain ERK extracellular signalregulated kinase
CXCL1 C-X-C motif ligand 1 ERP event-related potential
DA dopamine ES1 exteroreceptive suppression (silent) period 1
DAG diacylglycerol ESR erythrocyte sedimentation rate
DAP depolarizing afterpotential ESSIC European Society for the Study of Interstitial
DAT dopamine transporter Cystitis
DBS deep brain stimulation ET-1 endothelin 1
DC dendritic cell ETa endothelin receptor A
DCN dorsal column nuclei ETTH episodic tension-type headache
ddC 2,3-dideoxycytidine EULAR European League Against Rheumatism
ddI 2,3-dideoxyinosine FA fractional anisotropy
DDS-I Descriptor Differential Scale: intensity FAAH fatty acid amide hydrolase
dimension FAI femoral acetabular impingement (syndrome)
DEG/ENac degenerin/epithelial sodium channel FAPS functional abdominal pain syndrome
DGL FBSS failed back surgery syndrome
(DAGL) diacylglycerol lipase FCA Freunds complete adjuvant
DH dorsal horn FD functional dyspepsia
DHE dihydroergotamine FDA Food and Drug Administration
DHPG dihydroxyphenylglycine FGF broblast growth factor
DLPFC dorsolateral prefrontal cortex FGID functional gastrointestinal disorder
DMARD disease-modifying antirheumatic drug FHM familial hemiplegic migraine
DMSO dimethylsulfoxide FIESTA fast imaging employing steady-state acquisition
DN4 Douleur Neuropathique en 4 questions (MRI)
DNI distal nerve injury (model) FIQ Fibromyalgia Impact Questionnaire
DNIC diffuse noxious inhibitory control FISH uorescence in situ hybridization
DOMS delayed-onset muscle soreness FLACC Face, Legs, Activity, Cry, Consolability
DOR -opiate receptor FM bromyalgia
DPN diabetic painful neuropathy FMH familial hemiplegic migraine
DREAM downstream regulatory element antagonistic FMPL N-formylmethionyl-leucyl-phenylalanine
modulator fMRI functional magnetic resonance imaging
DREZ dorsal root entry zone FMS bromyalgia syndrome
DRG dorsal root ganglion FPS focal pain scale
DRR dorsal root reex FRAP uoride-resistant acid phosphatase
DSM-IV Diagnostic and Statistical Manual of Mental 5-FU 5-uorouracil
Disorders, 4th edition GA gestational age

GABA -aminobutyric acid IBS-M irritable bowel syndrome with

GAD glutamic acid decarboxylase mixed bowel habits
GAT-1 GABA transporter type 1 IC insular cortex; interstitial cystitis
GBS Guillain-Barr syndrome IC50 inhibitive concentration of 50%
G-CSF granulocyte colony-stimulating factor ICC intraclass correlation coefcient
GDNF glial cell linederived neurotrophic factor ICD-9 International Classication of Diseases, ninth
GEn gabapentin enacarbil revision
GERD gastroesophageal reux disease ICHD International Classication of Headache
GFAP glial brillary acidic protein Disorders
GHQ General Hospital Questionnaire ICSS intracranial self-stimulation
GI gastrointestinal IENF intraepithelial nerve ber
GIRK G-proteincoupled inward rectifying potassium IGLE intraganglionic laminar ending
channel IHS International Headache Society
Gly-IR glycine immunoreactivity IL interleukin
GlyR glycerine receptor IM intermediate metabolizer
GM-CSF granulocytemacrophage colony-stimulating iMA intramuscular array
factor IMMPACT Initiative on Methods, Measurements, and Pain
GON greater occipital nerve Assessment in Clinical Trials
GP general practitioner INCB International Narcotics Control Board
GPCR G proteincoupled receptor iNOS inducible nitric oxide synthase
GpER extended-release gabapentin INR international normalized ratio
GPN glossopharyngeal neuralgia IP3 inositol triphosphate
GREP Gender Role Expectations in Pain IPG implantable pulse generator
GRPR gastrin-releasing peptide receptor IPL inferior parietal lobule
GS gastrocnemiussoleus IPSC inhibitory post-synaptic current
GW gestational weeks IPSP inhibitory post-synaptic potential
GWAS genome-wide association study ISB interscalene brachial plexus blockade
HAART highly active antiretroviral therapy IT intrathecal
HADS Hospital Anxiety and Depression Scale ITS iontophoretic transdermal system
HC hemicrania continua IVRS intravenous regional sympatholysis
hCG human chorionic gonadotropin JCAHO Joint Commission on Accreditation of
HCN hyperpolarization-activated cyclic nucleotide Healthcare
gated (ion channel) JNK c-Jun N-terminal kinase
HD homeodomain K/C kaolin and carrageenan
HETE hydroxyeicosatetraenoic acid KCC2 potassiumchloride co-transporter-2
HGF hepatocyte growth factor K/L KellegrenLawrence (OA grading system)
HIT Headache Impact Test LANSS Leeds Assessment of Neuropathic Symptoms
HIV human immunodeciency virus and Signs (pain scale)
HLA human leukocyte antigen LASIK laser in situ keratomileusis
HNC healthy normal control LBP low back pain
HPC polymodal nociceptive cells LC locus coeruleus; Langerhans cell
HPETE hydroperoxyeicosatetraenoic (acid) LCP Liverpool Care Pathway for the Dying Patient
HPOA hypertrophic pulmonary osteoarthropathy LEP laser-evoked potential
HR heart rate LFS low-frequency stimulation
HRQoL health-related quality of life LGI1 leucine-rich inactivated 1
HRT hormone replacement therapy LHRF luteinizing hormonereleasing factor
HSAN hereditary sensory and autonomic neuropathy LHRH luteinizing hormonereleasing hormone
HSMN hereditary sensory and motor neuropathy LIDSI lack of information about diagnosis or severity
HSV herpes simplex virus of the illness
HT high-threshold (stimuli) LIF leukemia inhibitory factor
5-HT 5-hydroxytryptamine LIG leucine-rich repeat and immunoglobulin
HTN high-threshold (mechanoreceptor) LLI leg length inequality
mechanosensitive LLLT low-level laser therapy
5-HTP 5-hydroxytryptophan L-NAME N-nitro-l-arginine methyl ester
IA intra-articular L-NMA NG-methyl-l-arginine
IADR International Association for Dental Research L-NMNA NG-monomethyl-l-arginine hydrochloride
IASP International Association for the Study of Pain LOCF last observation carried forward
IB4 isolectin B4 LOX lipoxygenase
IBD inammatory bowel disease 5-Lox 5-lipoxygenase
IBS irritable bowel syndrome LP lumbar puncture
IBS-C irritable bowel syndrome with constipation LPb lateral parabrachial area
IBS-D irritable bowel syndrome with diarrhea LPS lipopolysaccharide

LS lumbosacral nAChR nicotinic acetylcholine receptor

LT low-threshold (stimuli) NADPH nicotinamide adenine dinucleotide phosphate
LTB4 leukotriene B4 NAPE N-arachidonylphosphatidylethanolamine
LTD long-term depression nBR nociceptive component of the blink reex
LTM low-threshold mechanoreceptive/ NCCP non-cardiac chest pain
mechanosensitive (cell, afferent) NDPH new daily persistent headache
LTP long-term potentiation NDSA non-dermatomal sensory abnormality
M1 primary motor cortex NE norepinephrine
MA mechanically activated NET norepinephrine transporter
MAO monoamine oxidase NF200 neurolament 200
MAP mitogen-activated protein (kinase) NFACS Neonatal Facial Action Coding System
MAPK mitogen-activated protein kinase NFCI non-freezing cold injury
mBSA methylated bovine serum albumin NF-B nuclear factor B
MCP-1 monocyte chemoattractant protein-1 NGF nerve growth factor
MCS motor cortex stimulation Ngn1 neurogenin 1
MD medial dorsal (nucleus) NGT nitroglycerin (glyceryl trinitrate)
MDD major depressive disorder NHANES National Health and Nutrition Examination
MDvc medial dorsal (nucleus), ventral caudal portion Survey
MeCP2 methyl CpG binding protein 2 NHP Nottingham Health Prole
M3G morphine-3-glucuronide NICU neonatal intensive care unit
M6G morphine-6-glucuronide NK natural killer (cell)
MEG magnetoencephalogram NK1 neurokinin 1
MEK mitogen-activated protein/ERK kinase NKA neurokinin A
MELAS mitochondrial encephalopathy, lactic acidosis, NMDA N-methyl-d-aspartate
and stroke-like episodes NNH number needed to harm
MEP magnetic evoked potential nNOS neuronal nitric oxide synthase
mEPSC miniature excitatory post-synaptic current NNQ number needed to harm
MFG medial frontal gyrus NNT number needed to treat
MFPS myofascial pain syndrome NO nitric oxide
MGL monoacylglycerol lipase NOS nitric oxide synthase
mGlu metabotropic glutamate (receptor) NP neuropathic pain
MGS mouse grimace scale NPQ Neuropathic Pain Questionnaire
MGUS monoclonal gammopathy of undetermined NPS Neuropathic Pain Scale
signicance NPFF neuropeptide FF
MHC major histocompatibility complex NPY neuropeptide Y
MIA mechanically insensitive afferent (afferent NRS numerical rating scale
bers); mono-iodoacetate (model) NS nociceptive-specic (cell)
MIDAS Migraine Disability Assessment Scale NSAID non-steroidal anti-inammatory drug
MINI Mini International Neuropsychiatric Interview NSAP non-specic arm pain
mIPSC miniature inhibitory post-synaptic current NSRI serotoninnorepinephrine reuptake inhibitor
MMPI Minnesota Multiphasic Personality Inventory NT3 neurotrophin 3; neurotrophic factor 3
MOR -opioid receptor NYHA New York Heart Association
MPEP 2-methyl-6-(phenylethynyl) pyridine OA osteoarthritis
MPI Multidimensional Pain Inventory OARSI Osteoarthritis Research Society International
MPQ McGill Pain Questionnaire OFC orbitofrontal cortex
MPS myofascial pain syndrome OIH opioid-induced hyperalgesia
mPP mitochondrial permeability pore OMERACT Objective Measures of Randomized Clinical
MRA magnetic resonance angiography Trials
mRFF minimum rhythmic ring frequency OMIM Online Mendelian Inheritance in Man
Mrgprd Mas-related G proteincoupled (database)
MRI magnetic resonance imaging ONJ osteonecrosis of the jaw
MRS magnetic resonance spectroscopy OR odds ratio
MS multiple sclerosis OSA obstructive sleep apnea
MSA mechanically sensitive afferent PACAP pituitary adenyl cyclaseactivating peptide
MSG monosodium glutamate PAD primary afferent depolarization
mTOR mammalian target of rapamycin PAF platelet-activating factor
MVD microvascular decompression PAG periaqueductal gray
MZ monozygotic PAOD peripheral arterial occlusive disease
N noradrenergic PAP prostatic acid phosphatase
NAA N-acetylaspartate PAR protease-activated receptor
NAc nucleus accumbens PASS Pain Anxiety Symptoms Scale
NAC N-acetylcysteine PB parabrachial nucleus (of the dorsolateral pons)

PBMC peripheral blood mononuclear cell PV partial ventral

PCA patient-controlled analgesia PVAS pain visual analog scale
PCEA patient-controlled epidural analgesia PVB cis-platinumvinblastinebleomycin
PCIA patient-controlled intravenous analgesia PVD peripheral vascular disease
PD personality disorder; Parkinsons disease PVG periventricular gray
PDA personal digital assistant QC quick C (ber)
PDI Pain Disability Index QoL quality of life
PDN painful diabetic neuropathy QSART quantitative sudomotor axon reex test
PDPH postdural puncture headache QST quantitative sensory test/testing; quantitative
PEA palmitoylethanolamine somatosensory thermotest
PEPD paroxysmal extreme pain disorder QTL quantitative trait locus
PET positron emission tomography RA rheumatoid arthritis
Pf parafascicular (nucleus) rACC rostral anterior cingulate cortex
PFC prefrontal cortex RAIC rostral anterior insular cortex
PFMS primary bromyalgia syndrome RANK receptor activator of NF-B
PG prostaglandin RANKL RANK ligand
pgACC perigenual anterior cingulate cortex rCBF regional cerebral blood ow
PGP protein gene product (e.g., PGP 9.5) RCT randomized controlled trial
PH paroxysmal hemicrania REM rapid eye movement (sleep)
PHN post-herpetic neuralgia RET receptor tyrosine kinase
PI3K phosphatidyl-3-kinase RF receptive eld
PIEB programmed intermittent epidural bolus RFT radiofrequency thermorhizotomy
PI-IBS postinfectious IBS r-HuEPO
PIP2 phosphatidylinositol 4,5-bisphosphate alfa recombinant human epoetin alfa
PIPP Premature Infant Pain Prole RLS restless legs syndrome
PKA protein kinase A RR relative risk
PKC protein kinase C RSD reex sympathetic dystrophy
PLA2 phospholipase A2 RSI repetitive strain injury
PLD phospholipase D rTMS repetitive transcranial magnetic stimulation
PLC phospholipase C RVM rostral ventromedial medulla; rostroventral
PLP phantom limb pain medulla
PLS phantom limb sensation S serotonergic
PM poor metabolizer SC slow C (ber)
PMN polymorphonuclear SCI spinal cord injury
PNB peripheral nerve block SCL-90R Symptom Checklist90 Revised
PNI peripheral nerve injury SCORE Serious Complication Repository
PNS parasympathetic nervous system; peripheral SCR skin conductance response
nervous system SCS spinal cord stimulation
Po posterior complex (nucleus) SCT spinocervicothalamic
POMS Prole of Mood States SDH supercial dorsal horn
PONV postoperative nausea and vomiting SDT sensory decision theory
PoT posterior triangular (nucleus) SEP somatosensory evoked potential
PPAR- peroxisome proliferatoractivated receptor SERP somatosensory event-related potential
PPT pressure pain threshold SERT serotonin transporter
PQAS Pain Quality Assessment Scale SF-36 36-item short form of the Medical Outcomes
Pr5 primary sensory trigeminal nucleus Society
PREP pain-related electrically evoked potential SFL spontaneous foot-lifting (behavior)
PRI pain rating index SF-MPQ short-form McGill Pain Questionnaire
PRI-A pain rating index (affective) SFMS secondary bromyalgic syndrome
PRI-S pain rating index (sensory) SG substantia gelatinosa
PRI-T pain rating index (total) SHT spinohypothalamic tract
PRK photorefractive keratectomy SI, SII primary and secondary somatosensory cortices
PROMIS Patient-Reported Outcome Measurement sIL-6R soluble IL-6 receptor
Information System SIP Sickness Impact Prole; sympathetically
PROSPECT Procedure-Specic Postoperative Pain independent pain
Management siRNA small interfering RNA
PSDC post-synaptic dorsal column pathway sLORETA source analysis method of low-resolution brain
PSNL partial sciatic nerve ligation (model) electromagnetic tomography; standardized
PSQI Pittsburgh Sleep Quality Index low-resolution brain electromagnetic
PT physical therapy tomography
PTCA percutaneous transluminal coronary angioplasty Sm submedius (nucleus)
PTSD post-traumatic stress disorder SMA supplementary/supplemental motor area

SMON subacute myelo-optic neuropathy TRAK-1 TWIK-related K+ channel 1

SMP sympathetically maintained pain TRESK TWIK-related spinal cord potassium channel
SNI spared nerve injury (model) trkA tyrosine kinase receptor A; tropomyosin-related
SNL spinal nerve ligation (model) kinase A
SNP single nucleotide polymorphism TRP transient receptor potential
SNRI serotoninnoradrenaline reuptake inhibitor TRPA1 transient receptor potential ankyrin 1
SNS sympathetic nervous system TRPV1 transient receptor potential vanilloid 1
SNSR sensory neuronsensitive receptor TST sectioning of the tibial and sural nerves while
SOPA Survey of Pain Attitude leaving the common peroneal nerve intact
SP substance P (model)
Sp5 spinal sensory trigeminal nucleus TTH tension-type headache
Sp5C spinal sensory trigeminal nucleus caudalis TTS total tenderness score
subnucleus TTX tetrodotoxin
Sp5I spinal sensory trigeminal nucleus interpolaris TTXr tetrodotoxin-resistant
subnucleus TUNEL terminal deoxynucleotidyl transfer nick end
Sp5O spinal sensory trigeminal nucleus oralis labeling
subnucleus TWIK tandem of P domains in a weak inward
SPECT single-photon emission computed tomography rectifying K+ channel
SPSAP substance Psaporin UK United Kingdom
SQUID superconductivity quantum induction device UM ultrarapid metabolizer
SRD subnucleus reticularis dorsalis UR unconditioned response
SRF serum response factor US unconditioned stimulus; United States
SSRI selective serotonin reuptake inhibitor UTP uridine triphosphate
SSS Somatic Symptoms Score UVB ultraviolet B
sst/SST somatostatin VAS visual analog scale
STAI StateTrait Anxiety Inventory Vc ventral caudal (nerve)
STD short-term depression VCAM vascular cell adhesion molecule
StEP Standardized Evaluation of Pain Vcpc parvicellular part of the ventral caudal (nucleus)
STh sensory thalamic (nuclei) VDS verbal descriptor scale
STP soft tissue pain (syndrome) VGAT vesicular GABA transporter
STT spinothalamic tract VGCC voltage-gated calcium channel
SUNA short-lasting unilateral neuralgiform headache VGLUT vesicular glutamate transporter
attacks VGSL voltage-gated sodium channel
SUNCT short-lasting unilateral neuralgiform headache VIP vasoactive intestinal polypeptide
attacks with conjunctival injection and tearing VL ventral lateral (nerve)
SV2A synaptic vesicle 2A VLO ventral lateral orbital (cortex)
SVC superior vena cava VMb basal part of the ventral medial (nucleus)
TA treatment adherence VMl ventromedial (thalamus)
TAC trigeminal autonomic cephalgia VMpo posterior part of the ventral medial (nucleus)
TASK TWIK-related acid-sensitive K+ channel VP ventral posterior (nucleus)
TBNS trigeminal brain stem nuclear complex VPI ventroposterior inferior (nucleus)
TCA tricyclic antidepressant VPL ventral posterior lateral (nucleus)
TCM traditional Chinese medicine VPM ventral posterior medial (nucleus)
TENS transcutaneous electric nerve stimulation VRP ventral root potential
TGF transforming growth factor VRS verbal rating scale
TGVS trigeminovascular system VTA ventral tegmental area
THC tetrahydrocannabinol VZV varicella-zoster virus
TL thoracolumbar WDR widedynamic range (cell neuron)
TLR toll-like receptor WHO World Health Organization
Tm transmembrane WPI Widespread Pain Index
TMD temporomandibular disorder WC workers compensation
TMJ temporomandibular joint WOMAC Western Ontario and McMaster (Universities)
TN trigeminal neuralgia Osteoarthritis Index
TNF- tumor necrosis factor- WS Waddells sign
TRAAK TWIK-related arachidonic acid K+ channel YAG yttriumaluminumgarnet

Section I Neurobiology of Pain Chapter 13 Autonomic, Endocrine, and

Immune Interactions in Acute
Chapter 1 Peripheral Mechanisms of and Chronic Pain 198
Cutaneous Nociception 1 Wilfrid Jnig and Jon D. Levine
Matthias Ringkamp, Srinivasa N. Raja,
James N. Campbell, and Richard A. Meyer Chapter 14 Itch 211
Martin Schmelz and Hermann O. Handwerker
Chapter 2 Molecular Biology of Sensory
Transduction 31
Michael S. Gold Section II Assessment and Psychology
of Pain
Chapter 3 Inammatory Mediators
and Modulators of Pain 48 Chapter 15 Gender Differences in Pain and
John M. Dawes, David A. Andersson, Its Relief 221
David L.H. Bennett, Stuart Bevan, Joel D. Greenspan and Richard J. Traub
and Stephen B. McMahon
Chapter 16 Epidemiology of Pain 232
Chapter 4 Microglia: Critical Mediators Gary J. Macfarlane, John McBeth, and
of Pain Hypersensitivity after Gareth T. Jones
Peripheral Nerve Injury 68
Simon Beggs and Michael W. Salter Chapter 17 Emotion, Motivation, and Pain 248
Ben Seymour and Ray J. Dolan
Chapter 5 Neuroanatomical Substrates
of Spinal Nociception 77 Chapter 18 Cognitive and Learning
Andrew J. Todd and H. Richard Koerber Aspects 256
Herta Flor and Dennis C. Turk
Chapter 6 Spinal Cord Plasticity and Pain 94
Jrgen Sandkhler Chapter 19 Psychiatric Pain-Associated
Co-morbidities 273
Chapter 7 Representation of Pain David A. Fishbain
in the Brain 111
A. Vania Apkarian, M. Catherine Bushnell, Chapter 20 Studies of Pain in Human
and Petra Schweinhardt Subjects 283
Richard H. Gracely
Chapter 8 Central Nervous System Mechanisms
of Pain Modulation 129 Chapter 21 Pain Measurement in Adult
Mary M. Heinricher and Howard L. Fields Patients 301
Ronald Melzack and Joel Katz
Chapter 9 Development of Pain Pathways
and Mechanisms 143 Chapter 22 Pain in Older Persons 315
Mark L. Baccei and Maria Fitzgerald Lucia Gagliese and Ronald Melzack

Chapter 10 Genetics of Pain 156 Chapter 23 Measurement and Assessment

Jeffrey S. Mogil, Mitchell B. Max, of Pediatric Pain 320
and Inna Belfer Patrick J. McGrath and Anita M. Unruh

Chapter 11 Animal Models of Pain 170 Chapter 24 Assessment of Pain Beliefs,

Odd-Geir Berge Coping, and Function 328
Jennifer A. Haythornthwaite
Chapter 12 Ascending Projection
Systems 182 Chapter 25 Hypnotic Analgesia 339
Jonathan O. Dostrovsky and A.D. (Bud) Craig Pierre Rainville and Donald D. Price



Chapter 26 Pain, Opiates, and Addiction 351 Chapter 42 The Cognitive-Behavioral Approach
Stephen P. Hunt and Catherine E. Urch to Pain Management 592
Dennis C. Turk and Herta Flor
Chapter 27 Placebo Analgesia 362
Tor D. Wager and Howard L. Fields Chapter 43 A Critical Appraisal of
Complementary and
Alternative Medicine 603
Section III Pharmacology and Treatment Edzard Ernst
of Pain
Chapter 28 Spinal Pharmacology of Section IV Clinical States/Deep Somatic
Nociceptive Transmission 375 Tissue
Linda S. Sorkin and Tony L. Yaksh
Chapter 44 Joint Pain: Basic Mechanisms 609
Chapter 29 Methods of Therapeutic Trials 402 Hans-Georg Schaible
Henry J. McQuay and Andrew Moore
Chapter 45 Basic Mechanisms of
Chapter 30 Opioids: Basic Mechanisms 413 Muscle Pain 620
Anthony H. Dickenson and Brigitte L. Kieffer Siegfried Mense
Chapter 31 Opioids: Clinical Use 429 Chapter 46 Postoperative Pain and
Stephan A. Schug
Its Management 629
Asokumar Buvanendran, Timothy R. Lubenow,
Chapter 32 Cyclooxygenase Inhibitors: and Jeffrey S. Kroin
Basic Aspects 444
Hanns Ulrich Zeilhofer and Kay Brune Chapter 47 Osteoarthritis and
Rheumatoid Arthritis 645
Chapter 33 Cyclooxygenase Inhibitors: Tuhina Neogi and David Felson
Clinical Use 455
Andrew Moore and Henry J. McQuay Chapter 48 Fibromyalgia Syndrome and
Myofascial Pain Syndrome 658
Chapter 34 Antidepressant Analgesics 465 I. Jon Russell
C. Peter N. Watson, Ian Gilron, Bruce G. Pollock,
Arthur G. Lipman, and Maree T. Smith
Chapter 49 Low Back Pain 683
Maurits van Tulder and Bart Koes
Chapter 35 Mechanism of Action of
Anticonvulsants as Chapter 50 Non-specic Arm Pain 694
Analgesic Drugs 491 Andrew Dilley and Jane Greening
Valerie Morisset, John B. Davis, and Simon N. Tate

Chapter 36 Anticonvulsants: Clinical 500 Section V Clinical States/Viscera

Zahid Ali, Joanne E. Palmer,
and Veeraindar Goli Chapter 51 Visceral Pain: Basic
Mechanisms 703
Chapter 37 Local Anesthetic Blocks Klaus Bielefeldt and Gerald F. Gebhart
and Epidurals 523
Harald Breivik Chapter 52 Thoracic Pain 718
Allan Gottschalk and E. Andrew Ochroch
Chapter 38 Cannabinoids 538
Andrea G. Hohmann and Andrew S.C. Rice Chapter 53 A Clinical Perspective
on Abdominal Pain 734
Chapter 39 Analgesic Drugs Emeran A. Mayer, Arpana Gupta,
in Development 552 and Heng Yu Wong
Raymond G. Hill
Chapter 54 Genitourinary Pain 758
Chapter 40 Neurosurgical Approaches Timothy J. Ness and Promil Kukreja
to the Treatment of Pain 563
Michael J. Dorsi and Fred A. Lenz Chapter 55 Obstetric Pain 772
Peter H. Pan
Chapter 41 Spinal Cord and Brain
Stimulation 570
Bengt Linderoth and Bjrn A. Meyerson

Section VI Clinical States/Headache and Chapter 67 Complex Regional Pain

Facial Pain Syndromes 961
Andreas Binder and Ralf Baron
Chapter 56 Trigeminal Mechanisms
Chapter 68 Pain Following Spinal Cord
of Nociception 793
Luis Villanueva and Rodrigo Noseda Injury 978
Paul J. Wrigley and Philip J. Siddall
Chapter 57 Acute and Chronic Orofacial
Chapter 69 Central Pain 990
and Dental Pain 803 Troels Staehelin Jensen and Nanna Brix Finnerup
Jennifer L. Gibbs and Kenneth M. Hargreaves
Chapter 70 Pharmacological Therapy of
Chapter 58 Migraine and the Trigeminal
Neuropathic Pain 1003
Autonomic Cephalalgias 815 Thomas R. Toelle and Miroslav (Misha) Bakonja
Peter J. Goadsby
Chapter 71 Surgery for Back and Neck Pain
Chapter 59 Tension-Type Headache 832
Jean Schoenen and Simona Liliana Sava (Including Radiculopathies) 1012
Donlin M. Long
Chapter 60 Pain in and around the Eye 843
Carlos Belmonte and Timo T. Tervo
Section VIII Clinical States/Cancer Pain
Section VII Clinical States/Neuropathic Pain Chapter 72 Cancer Pain: Causes,
Consequences, and Therapeutic
Chapter 61 Neuropathic Pain: Pathophysiological Opportunities 1029
Response of Nerves to Injury 861 Patrick W. Mantyh
Marshall Devor
Chapter 73 Cancer Pain Assessment
Chapter 62 Animal Models of Experimental and Syndromes 1039
Neuropathic Pain 889 Nathan I. Cherny
Michael H. Ossipov and Frank Porreca
Chapter 74 Analgesic Therapy and Palliative
Chapter 63 Central Consequences of Peripheral Care in Children 1061
Nerve Damage 902 Charles B. Berde and John J. Collins
Tomas G.M. Hkfelt, Xu Zhang, Marcelo Villar,
Xiao-Jun Xu, and Zsuzsanna Wiesenfeld-Hallin Chapter 75 Cancer Pain: Treatment
Overview 1075
Chapter 64 Phantom Limb 915 Peter Hoskin and Karen Forbes
Lone Nikolajsen
Chapter 76 Pain Control in the Care of
Chapter 65 Painful Peripheral the Dying 1092
Neuropathies 926 John E. Ellershaw and Andrew Dickman
John W. Scadding and Martin Koltzenburg

Chapter 66 Trigeminal and Glossopharyngeal

Neuralgia 952
Joanna Maria Zakrzewska, H. Issac Chen,
and John Y.K. Lee
Neurobiology of Pain
Chapter Peripheral Mechanisms
of Cutaneous Nociception
1 Matthias Ringkamp, Srinivasa N. Raja, James N. Campbell,
and Richard A. Meyer

this function. In this chapter we consider the peripheral neu-

SUMMARY ral apparatus that responds to noxious (injurious or poten-
Nociceptors are a specialized class of primary afferents tially injurious) stimuli and thus provides a signal to alert
that respond to intense, noxious stimuli. Unmyelinated the organism to potential injury. Investigators have studied
nociceptors signal the burning pain from intense heat cutaneous sensibility by recording from single nerve bers in
stimuli applied to the glabrous skin of the hand, as different species, including humans. Stimuli are applied to the
well as the pain from sustained pressure. Myelinated receptive eld (i.e., area of the tissue responsive to the applied
nociceptors signal the sharp pain from heat stimuli stimulus) of single bers, and the characteristics of the neu-
applied to hairy skin and from sharp mechanical stim- ral response are noted. We concentrate on the skin for three
uli. Both myelinated and unmyelinated nociceptors reasons. First, sensory receptors in the skin have been more
signal pain from chemical stimuli. Following a cuta- thoroughly studied than receptors in any other tissue. Second,
neous injury, enhanced pain in response to cutaneous the opportunity to perform correlative psychophysical stud-
stimuli, called hyperalgesia, develops at the site of ies in animals and humans allows powerful inferences to be
injury (primary hyperalgesia) and in the surrounding made regarding function. Third, cutaneous pain sensation is
uninjured skin (secondary hyperalgesia). Tissue injury of great clinical signicance. Diseases such as post-herpetic
leads to enhanced responsiveness of nociceptors, neuralgia and others associated with small-ber neuropathies
called sensitization, which accounts for primary hyper- have profound effects on cutaneous sensory function and
algesia. This sensitization is due to the local release often lead to severe pain.
of inammatory mediators. Secondary hyperalgesia is Highly specialized sensory bers, alone or in concert with
due to sensitization of neurons in the central nervous other specialized bers, provide information to the central
system. When nerves are severed, spontaneous activity nervous system (CNS) not only about the environment but
and ectopic mechanical, thermal, and chemical sensi- also about the state of the organism itself. In the case of the
tivity develop in the injured nociceptors. The proper- sensory capacity of the skin, cutaneous stimuli may evoke
ties of nearby, uninjured nociceptors are also changed. a sense of cooling, warmth, or touch. Accordingly, certain
In both injured and uninjured nociceptors, responsive- sensory bers are selectively sensitive to these stimuli. Warm
ness to adrenergic agents can develop, which may bers, which are predominately unmyelinated, are exquisitely
account for involvement of the sympathetic nervous sensitive to gentle warming of their punctate receptive elds.
system in certain forms of neuropathic pain. These bers have been shown to exclusively signal the quality
and intensity of the warmth sensation (Johnson et al 1979).
Similarly, a subpopulation of the thinly myelinated, A bers
respond selectively to gentle cooling stimuli and encode the
INTRODUCTION sense of cooling (Darian-Smith et al 1973). For the sense of
touch, different classes of mechanoreceptive afferent bers are
One of the vital functions of the nervous system is to provide exquisitely sensitive to deformations of the skin. These low-
information about the occurrence or threat of injury. The sen- threshold mechanoreceptors encode such features as texture
sation of pain, by its inherent aversive nature, contributes to and shape.

2 Section One | Neurobiology of Pain

A relatively high threshold for an adequate stimulus distin- squeezing (mechanical) stimuli to the skin and thus identify
guishes the remaining class of cutaneous receptors. Because the receptive eld. This selection process identies what are
these receptors respond preferentially to noxious stimuli, they termed mechanically sensitive afferents (MSAs). In time it has
are termed nociceptors (Sherrington 1906). Among the many become apparent that selection bias from this approach has
varieties of sensory receptors, nociceptors are distinctive in led to oversight of an important class of nociceptors: mechan-
that they typically respond to the multiple energy forms that ically insensitive afferents (MIAs). Because these bers by def-
produce injury (thermal, mechanical, and chemical stimuli) inition have high mechanical thresholds (or are unresponsive
and provide information to the CNS regarding the location to mechanical stimuli), nding the mechanical receptive eld
and intensity of noxious stimuli. Nociceptors may be subclas- of these bers is difcult. An alternative technique described
sied with respect to four criteria: (1) unmyelinated C-ber by Meyer and colleagues (1991) has been to apply electrical
afferents (conduction velocity <2 m/sec) versus myelinated stimuli to the skin to identify the putative receptive eld. With
A-ber afferents (conduction velocity >2 m/sec), (2) modali- this technique it turns out that about half of the A-ber noci-
ties of stimulation that evoke a response, (3) response charac- ceptors and 30% of the C-ber nociceptors are MIAs, with
teristics, and (4) distinctive chemical markers (e.g., receptors MIAs being dened as afferents that have very high mechani-
expressed on the membrane). We rst consider the properties cal thresholds (>6 bar = 600 kPa = 60 g/mm2) or are unrespon-
of cutaneous nociceptors and then review how their function sive to mechanical stimuli (Handwerker et al 1991, Meyer
is thought to relate to the sensation of pain. et al 1991). MIAs have also been reported in the knee joint
Tissue damage results in a cascade of events that lead to (Schaible and Schmidt 1985), viscera (Hbler et al 1988), and
enhanced pain in response to natural stimuli, termed hyperal- cornea (Tanelian 1991). As will be seen, this MIAMSA dis-
gesia. A corresponding increase in the responsiveness of noci- tinction is of signicance with regard to distinguishing noci-
ceptors, called sensitization, occurs. The characteristics of ceptor types. From the perspective of nomenclature, it is well
hyperalgesia and its neurophysiological counterpart sensitiza- to emphasize that MIAs are not dened as bers that have no
tion are discussed in a later section. Finally, we consider how response to mechanical stimuli but rather as bers that have a
nociceptors may play a role in accounting for the often severe very high threshold (or no sensitivity at all) such that demon-
pain that accompanies nervous system injury and disease. stration of a response to mechanical stimuli in electrophysi-
ological studies is difcult.
IN UNINJURED SKIN C-Fiber Nociceptors
Nature might have designed nociceptors such that each had CMHs are commonly encountered cutaneous afferents, and
the capacity to respond to the full complement of stimulus activity of sufcient magnitude in these bers is thought to
energy forms that pose potential risks to the organism (ther- evoke a burning pain sensation. The size of the receptive eld
mal, mechanical, and chemical). What nature has adopted appears to scale with the size of the animal. Typical values for
instead is a mixed strategy whereby many nociceptors respond monkey are between 15 and 20 mm2 (LaMotte and Campbell
to multiple stimulus modalities (polymodal) and others have 1978), and for human they are near 100 mm2 (Schmidt et al
more specialized response properties. These specialized 1997). There are often discrete areas of mechanical sensitiv-
response properties probably at least in part account for dif- ity (hot spots) within the receptive eld, but in many bers
ferent aspects of nociceptive sensory function (e.g., burning, the areas of mechanical responsiveness tend to fuse over the
aching, pricking, prickle, itch). As delineated later, nocicep- region of the receptive eld. Most CMHs respond to chemical
tors have distal effector functions as well, and specialization stimuli (though not as well as A-ber nociceptors; Davis et al
may also play a role here. The end result is that nociceptors 1993b) and can therefore be considered polymodal.
have a complex biology and heterogeneous properties. Responses to heat stimuli have been studied in consider-
The receptive eld of a nociceptor is often rst localized by able detail. The response of a typical CMH to a random
use of mechanical stimuli. Various other stimulus modalities sequence of heat stimuli ranging from 4149C is shown in
are then applied to this receptive eld. In most early studies Figure 1-1A. It can be seen that the response increases mono-
of nociceptors, only heat and mechanical stimuli were used to tonically with stimulus intensity over this temperature range,
study nociceptors. Therefore, the nomenclature of CMH and which encompasses the pain threshold in humans. One ion
AMH is often used to refer to C-ber mechano-heatsensitive channel involved in the transduction of heat at nerve termi-
nociceptors and A-ber mechano-heatsensitive nociceptors, nals is thought to be the neuronal transient receptor potential
respectively. If a ber responds to heat and mechanical stim- ion channel V1 (TRPV1); activity in this channel increases
uli, the ber will in most cases respond to chemical stimuli as with increasing temperature (Caterina et al 1997). A detailed
well (Davis et al 1993b). Thus, CMHs and AMHs may also description of the neuronal ion channels involved in stimulus
be referred to as polymodal nociceptors. transduction is presented in Chapter 2 (for review see Dubin
The issue of whether a given nociceptor responds to a par- and Papapoutian 2010). Signal transduction molecules on
ticular stimulus modality is perilous because the presumed keratinocytes may also play a role in heat transduction by
lack of response to a given modality may in fact represent inducing the release of adenosine triphosphate (ATP), which
failure to apply the stimulus with sufcient intensity. The activates purinergic receptors (P2X3 and P2Y2) on the free
problem with the application of high-intensity stimuli is that nerve endings (see Fig. 1-4).
the stimulus may alter the properties of the nociceptor in an Two types of heat response are observed following a
enduring manner. A selection bias occurs: nociceptors with stepped heat stimulus. Quick C (QC) bers exhibit their
lower thresholds are more likely to be studied. The easiest way peak discharge during the rising phase of the heat stimulus,
to nd a nociceptor for electrophysiological study is to apply whereas slow C (SC) bers exhibit their peak discharge during

the plateau phase (Fig. 1-2B). The heat thresholds (Fig. 1-2C) to the second of two identical heat stimuli is substantially less
and mechanical thresholds of QC bers are signicantly than the response to the rst stimulus. This fatigue is depen-
lower than those of SC bers, thus suggesting that they may dent on the time between stimuli, with full recovery taking
be located more supercially in the epidermis. QC bers longer than 10 minutes. A similar reduction in the intensity
respond more vigorously to pruritic stimuli than do SC bers, of pain after repeated heat stimuli is observed in human sub-
which suggests that they may be important in itch sensations jects (LaMotte and Campbell 1978). Fatigue is also appar-
(Johanek et al 2008). ent in Figure 1-1A, where the response to a given stimulus
Thermal modeling studies combined with electrophysi- varied inversely with the intensity of the preceding stimulus.
ological analysis have indicated that (1) the heat threshold of A decrease in the response to heat is also observed following
CMHs depends on the temperature at the depth of the receptor mechanical stimuli applied to the receptive eld or electrical
and not the rate of increase in temperature, (2) transduction stimuli applied to the nerve trunk (Peng et al 2003). This sug-
of heat stimuli (conversion of heat energy to action potentials) gests that fatigue in response to a given stimulus modality can
occurs at different skin depths for different CMHs (Tillman be induced by heterologous stimulation, that is, by excitation
et al 1995b), and (3) suprathreshold responses of CMHs vary with a stimulus of a different modality. Interestingly, recovery
directly with the rate of increase in temperature (Tillman from cross-modal or heterologous fatigue is faster than recov-
et al 1995a, 1995b; Yarnitsky et al 1992). The depth of the ery from fatigue induced by a stimulus of the same modality.
heat-responsive terminals of CMHs varies quite widely (rang- Presumably, this is because these heterologous stimuli do not
ing from 20570 m; Tillman et al 1995b). When a stepped activate and therefore do not fatigue the stimulus transduc-
temperature stimulus is applied to the skin, the temperature tion apparatus in the same way. Alternatively, fatigue may
increases in the subsurface levels more slowly because of ther- arise from independent effects on spike initiation (from anti-
mal inertia. The disparity in the surface temperature and the dromic stimulation) and transduction (from natural stimula-
temperature at the level of the receptor varies directly with tion at the receptive eld). Fatigue in response to heat stimuli
depth and indirectly with time. Given that the depth of CMH is also seen in vitro when small (and presumably nociceptive)
terminals varies widely, true heat thresholds are obtained dorsal root ganglion (DRG) cells are repetitively tested with
when the rate of increase in temperature is very gradual or heat stimuli (Greffrath et al 2002). The enhanced response, or
when the duration of the stimulus is very long. Although the sensitization, that may occur in CMHs after tissue injury is
literature reects a wide range of heat thresholds for CMHs, described below in the section on hyperalgesia.
when tested with these types of heat stimuli, the heat thresh- Responses to mechanical stimuli are covered in more detail
old of the majority of CMHs is in a remarkably narrow range later. Sufce it here to indicate that CMHs usually display
of 3941C (Tillman et al 1995b). a slowly adapting response to mechanical stimuli of a given
The response of CMHs is also strongly inuenced by the force. As noted later, MSA CMHs have a graded response to
stimulus history. Both fatigue and sensitization are observed. punctate stimuli, but their stimulusresponse functions become
One example of fatigue is the observation that the response saturated at levels substantially below the threshold for pain.


30 Low
Low (41 or 43C)
Impulses in first 3 s

40 Average
Impulses in first 3 s


(47 or 49C)
10 High

0 0
41 45 49 41 45 49
Stimulus temperature (C) Stimulus temperature (C)

Figure 1-1. Responses of a typical C-ber nociceptor and a warm ber to heat stimuli. Heat stimuli ranging from 41-49C and lasting 3 seconds
were presented at 25-second interstimulus intervals to the glabrous skin of the monkey hand. Each stimulus occurred with equal frequency and was preceded
by every other stimulus an equal number of times. Within these constraints, the order of stimulus presentation was randomized. Base temperature between
stimuli was 38C. A, Monotonic stimulusresponse function for a typical nociceptor. B, Non-monotonic stimulusresponse function for a typical warm ber.
The solid line represents the total response to a given temperature averaged across all presentations. The dotted lines represent the stimulusresponse func-
tions obtained when the preceding temperature was of low (41 and 43C) or high (47 and 49C) intensity. (Reproduced with permission from LaMotte RH,
Campbell JN 1978 Comparison of responses in warm and nociceptive C-ber afferents in monkey with human judgements of thermal pain. Journal of
Neurophysiology 41:509528.)
4 Section One | Neurobiology of Pain

C-ber MIAs are heterogeneous with regard to responses to pronounced chemosensitivity, these bers have some other
to chemical and heat stimuli, and some respond only to interesting properties that could account for pain in response
mechanical stimuli (but of course with a very high mechanical to tonic pressure stimuli or the neurogenic are response (see
threshold). The sensitivity to mechanical stimuli has no obvi- below).
ous correlation to the heat threshold (Davis et al 1993b). In Low-threshold C-ber mechanoreceptors that do not re-
contrast to CMH afferents, some C-ber MIAs in humans are spond to heat have been described in the cat (Bessou and Perl
vigorously excited when challenged with histamine or capsa- 1969) and rabbit (Shea and Perl 1985). In primates, including
icin. In addition, the activity observed in these C-ber MIAs humans, these bers have been found in proximal areas of
parallels the duration of the perception of itch (histamine) the body (Kumazawa and Perl 1977, Nordin 1990) and the
or burning pain (capsaicin) (Schmelz et al 1997, 2000b). hairy skin on the forearm (Vallbo et al 1999). These affer-
C-ber MIAs may therefore act as chemosensors. In addition ents are strongly activated by innocuous mechanical stimuli
moved slowly across the receptive eld, but they also respond
to pinprick stimuli. The neuronal activity in these bers is not
critical for the perception of touch and, according to one im-
A aging study, leads to the activation of the insular but not the
50 sensory cortex (Olausson et al 2003). Low-threshold C-ber
48 mechanoreceptors are thought to mediate the sensation of
Temperature (C)

46 pleasant touch and may therefore play an important role in

44 afliative behavior (Vallbo et al 1999, Wessberg et al 2003,
42 Lken et al 2009).
40 Some mechano-insensitive C bers are reported to be acti-
38 vated by non-noxious and noxious cold and hot stimuli. It has
36 been hypothesized that activity in these afferents may mediate
the hotburning sensations caused by such stimuli. These
afferents may also be involved in mediating psychophysical
phenomena such as paradoxical heat or the thermal grill
illusion (Campero et al 2009).
100 C-ber afferents differ not only in their receptive features
Frequency (Hz)

QC but also in their conductive properties. In fact, their con-

ductive and receptive properties appear to correlate. When
10 unmyelinated C-ber afferents are activated repetitively by
electrical stimuli, their conduction latency increases gradu-
ally (i.e., the conduction velocity of the afferent decreases). In
addition, with increasing stimulation frequency, the amount
of this activity-dependent slowing increases. Slowing in
0.1 C-ber MIAs is greater than in C-ber MSAs (Weidner et al
Time (s) 1999), and mechanosensitive nociceptive afferents show more
pronounced slowing than do cold-sensitive C bers, low-
12 threshold C bers, or sympathetic efferent C bers (Gee et al
QC (n = 22) 1996, Serra et al 1999, Obreja et al 2010, Ringkamp et al
10 SC (n = 21) 2010). This difference in slowing properties indicates that
the ion channels responsible for conduction may be different
8 and suggests that the ion channels responsible for spike initia-

tion at the receptive terminal may also differ between C-ber

A-Fiber Nociceptors
A-ber nociceptors are thought to evoke pricking pain, sharp-
0 ness, and perhaps aching pain. As a general rule, A-ber
36 38 40 42 44 46 48 50 52 nociceptors do what C-ber nociceptors do, but do it more
Temperature (C) robustly. They respond at higher discharge frequencies, and
the discriminable information supplied to the CNS is greater
Figure 1-2. Two types of heat responses are observed in C-ber noci- (e.g., Slugg et al 2000).
ceptors. A, Stepped heat stimulus (49C, 3 seconds) used to classify heat Two types of A-ber nociceptors are apparent (Dubner
response. B, The quick C (QC) ber (yellow circles) exhibits a high-frequency
discharge during the rising phase of the stimulus that adapts quickly (within et al 1977, Treede et al 1998). A summary of their properties
1 second). The slow C (SC) ber (blue circles) exhibits a relatively uniform is presented in Table 1-1. Type I bers are typically responsive
discharge throughout the stimulus period. Each circle represents the time to heat, mechanical, and chemical stimuli and may therefore
of occurrence of an action potential. C, A histogram of the heat thresholds be referred to as AMHs or polymodal nociceptors. Because
reveals that the distributions of QC and SC bers are almost non-overlapping.
(From Johanek LM, Meyer RA, Friedman RM, et al 2008 A role for poly-
the heat thresholds are high with short-duration stimuli (typi-
modal C-ber afferents in nonhistaminergic itch. Journal of Neuroscience cally >53C), the responsiveness of these bers to heat has
28:76597669.) in some studies been overlooked. Consequently, these bers

have been called high-threshold mechanoreceptors (HTMs) hot spots in response to mechanical stimuli is much more
by many investigators (e.g., Burgess and Perl 1967). Heat obvious.
sensitivity in type I bers is most likely mediated by the vanil- Type II A-ber nociceptors were encountered only infre-
loid receptorlike protein 1 (VRL1, renamed TRPV2) since quently in early studies. It turns out that this is because the
it has a similar high threshold for activation by heat and is thresholds to mechanical stimuli place the majority of these
expressed in neurons with small myelinated axons (Caterina bers in the MIA category. Many have no demonstrable
et al 1999). When heat thresholds are determined with long- response to mechanical stimuli. When an unbiased electrical
duration temperature stimuli, however, thresholds are in the search stimulus is used, however, the prevalence of type I and
mid-4050C range (Treede et al 1998). Type I AMHs are type II A-ber nociceptors in the hairy skin of the primate is
seen in hairy and glabrous skin (Campbell et al 1979) and similar. They do not occur in the glabrous skin of the hand
have also been described in the cat and rabbit (Fitzgerald and (where type I AMHs are prevalent). Their mean conduction
Lynn 1977, Roberts and Elardo 1985). The mean conduc- velocity, 15 m/sec, is also lower than that of type I AMHs.
tion velocity of type I AMHs in the monkey is 25 m/sec and Their responses to heat resemble those observed in CMHs,
extends as high as 55 m/sec. Thus, by conduction velocity and they may also be mediated by the vanilloid receptor 1
criteria, type I AMHs fall into a category between that of A (VR1 or TRPV1). Responses to endogenous inammatory/
and A bers. Nearly all type I AMHs are MSAs. Their recep- algesic mediators resemble those seen with type I A-ber noci-
tive eld size is similar to that of CMHs, but the presence of ceptors (Davis et al 1993b).
Examples of the differing responses of the two types of
A-ber nociceptors to a heat stimulus are shown in Figure
Table 1-1 Comparison of Type I and Type II A-Fiber 1-3. Type I bers exhibit a distinctive, gradually increasing
Nociceptors response to heat. They sensitize to burn and chemical injury
and probably play a role in the development of hyperalgesia.
Type II bers respond to heat in similar fashion to CMHs:
Heat threshold to short stimuli High Low early peak frequency and a slowly adapting response (Treede
Heat threshold to long stimuli Low Low et al 1995). As noted later, type II A-ber nociceptors are
Response to intense heat Slowly increasing Adapting thought to signal rst pain sensation in response to heat and
may also contribute to pain caused by the application of cap-
Response latency to intense heat Long Short
saicin to the skin (Ringkamp et al 2001).
Peak latency to intense heat Late Early The conduction velocity of small myelinated A bers
Mechanical threshold Most are MSAs Most are MIAs is, by denition, faster than that of unmyelinated C bers.
Conduction velocity A and A bers A bers
However, the terminal cutaneous branches of nociceptive A
bers may conduct at a velocity characteristic of unmyelin-
Sensitization to heat injury Yes No ated bers (i.e., <2 m/sec) (Peng et al 1999). In addition, these
Location Hairy and Hairy skin unmyelinated terminals may branch off the main axon several
glabrous skin centimeters proximal to their cutaneous receptive eld.
MIAs, mechanically insensitive afferents; MSAs, mechanically sensitive afferents.

100.0 10 Type I
AP rate (Hz)


Peak latency (s)

0 5 10 15 20 25 30

1.0 C 15 Type II
AP rate (Hz)

0.1 Type I
Type II

0.1 1 10 100 0 5 10 15 20 25 30
Response latency (s) Time (s)

Figure 1-3. A-ber nociceptors exhibit two types of responses to a heat stimulus. A, Scatter plot of peak discharge latency versus response latency for
mechanically insensitive afferents (MIAs; purple symbols) and mechanically sensitive afferents (MSAs; green symbols) in response to a 53C, 30-second stimu-
lus. Receptors that had a long peak discharge latency were considered to have a type I heat response (squares). Receptors that had a short response latency
and a peak discharge near stimulus onset were considered to have a type II heat response (circles). The type II heat response was found more frequently in the
MIA group (p 0.05, -test). B, Average peristimulus frequency histogram (obtained with a 0.2-second bin width) of the response to the 53C, 30-second
stimulus for A-ber nociceptors that had a type I heat response. C, Average peristimulus frequency histogram for A-ber nociceptors that had a type II heat
response. (Reproduced with permission from Treede RD, Meyer RA, Campbell JN 1998 Myelinated mechanically insensitive afferents from monkey hairy
skin: heat-response properties. Journal of Neurophysiology 80:10821093.)
6 Section One | Neurobiology of Pain

Nociceptors Can Be Classied the encoding genes were identical to some of the previously
by Molecular Markers described Mrgs were identied shortly thereafter (Lembo
et al 2002). For some Mrgs (MrgAC) identied in mice, no
The anatomical and biochemical features of nociceptive afferents ortholog genes exist in human or non-human primates, but
have been studied extensively to correlate these features with their closely related Mrgs (so-called MrgXs) have been identied.
receptive properties. A wide range of cell markers have been used For other Mrgs (MrgDG), however, ortholog genes exist in
to classify nociceptive afferents and to study their peripheral and humans. Mrgs are expressed mainly in non-peptidergic, IB4-
central projections. These markers include molecules expressed positive neurons, with some Mrgs being expressed in distinct
on the cell surface (e.g., receptors, glycoconjugates), molecules IB4 subpopulations. In in vitro recordings, MrgD+ DRG cells
stored and released from nociceptive afferents (e.g., peptides), showed characteristics typical of nociceptors (e.g., broad
and enzymes. Expression of receptors for neurotrophic factors is action potentials, expression of tetrodotoxin [TTX]-resistant
of interest since these factors may regulate the sensitivity of noci- sodium channels) (Drussor et al 2008). Receptors encoded
ceptive afferents in physiological and pathological states such as by Mrgs respond to a variety of ligands, including -alanine,
inammation and neuropathy. The size of neuronal populations cortistatin, peptides derived from different opioid precursors,
expressing or co-expressing different markers varies between and different RFamide peptides (Dong et al 2001, Han et al
species (Zwick et al 2002) and changes with the developmental 2002, Lembo et al 2002, Robas et al 2003, Shinohara et al
stage (Molliver et al 1997, Guo et al 2001). Inammation of 2004), and they probably modulate excitability and sensitiv-
the innervated tissue or a peripheral nerve lesion can cause sub- ity in this class of nociceptive afferents.
stantial changes in the expression of these molecules. With the Expression of some markers appears to be related to the
ongoing discovery of new marker molecules and the renement peripheral target tissue innervated by the neuron. Thus,
of histological techniques, classication of nociceptive afferents almost all visceral afferents are peptidergic, but only about
is undergoing constant change and revision. Despite these chal- half the afferents projecting to the skin are (e.g., Perry and
lenges, however, classication of nociceptive afferents based on Lawson 1998) and only a small percentage of afferents pro-
the expression of biochemical markers is instructive inasmuch as jecting to muscle are labeled with IB4 (Plenderleith and Snow
certain different neuronal populations are distinguishable across 1993, Ambalavanar et al 2003). MrgD-positive bers exclu-
species. Sophisticated genetic manipulations have allowed the sively innervate the skin, and they terminate in more super-
peripheral and central projections of dened neuronal popula- cial skin layers than do their peptidergic counterparts (Fig.
tions to be studied in great detail. In addition, ablation experi- 1-4) (Zylka et al 2005). Peptidergic and non-peptidergic affer-
ments have been used to study the role of dened neuronal ents project to distinct dorsal horn laminae, with peptider-
populations in animal behavior. gic bers projecting mainly to lamina I and lamina II outer
The cell bodies of nociceptive somatic and visceral affer- and IB4-binding afferents projecting preferentially to lamina
ents are located in DRGs. Slowly conducting A and C II inner (e.g., Hunt and Rossi 1985, Silverman and Kruger
bers, including nociceptors, have small cell bodies (Lawson 1988b; but see also Woodbury et al 2000).
and Waddell 1991). Some of these are labeled with an anti- Although all nociceptive neurons depend on nerve growth
body directed against a neurolament protein (NF200) and factor (NGF) during early development, in the adult only pepti-
are therefore thought to correspond to the somata of small dergic neurons express its receptor TrkA (tropomyosin-related
myelinated A afferents. kinase A) (Averill et al 1995). In contrast, most IB4-positive
Small DRG cells are subdivided into peptidergic neurons DRG cells do not express TrkA (Molliver et al 1995, but see
(i.e., neurons containing peptides such as substance P [SP], also Kashiba et al 2001) but express one of the glial-derived
calcitonin generelated peptide [CGRP], and somatostatin neurotrophic factor (GDNF) family receptors (GDNFR14)
[SST]) and non-peptidergic neurons. In the rat, about 40% together with receptor tyrosine kinase Ret (Bennett et al 1998,
of DRG cells, 50% of C bers, and 20% of A bers are Orozco et al 2001).
classied as peptidergic (McCarthy and Lawson 1989, Law- Peptidergic and non-peptidergic neurons express different
son et al 1996). Non-peptidergic, nociceptive neurons contain receptors involved in signal transduction, and they may there-
uoride-resistant acid phosphatase (FRAP) (Silverman and fore display different sensitivity to a given stimulus. Thus the
Kruger 1988a), and their somata and axons bind the plant P2X3 receptor, which mediates nociceptor excitation by ATP,
isolectin B4 (IB4) from Griffonia simplicifolia (Silverman and is primarily expressed in IB4-positive neurons (Vulchanova
Kruger 1988b). It is common practice to classify neurons as et al 1998). In contrast, TRPV1, which mediates responses to
peptidergic or non-peptidergic based on their binding of heat, capsaicin, and protons, is expressed in only a minority
IB4. However, considerable co-localization of SP or CGRP of IB4-positive cells in mice (Zwick et al 2002). In rats, how-
and IB4 or FRAP has been reported in rats but less so in mice ever, this segregation is less obvious since about half of both
(Carr et al 1990, Wang et al 1994, Bergman et al 1999, Price IB4-positive and -negative cells express TRPV1 (Caterina et al
and Flores 2007). In vivo intracellular recordings combined 1997; Michael and Priestley 1999; Guo et al 1999, 2001).
with immunohistochemistry have shown that cells contain- Species differences also exist in the co-expression of different
ing SP or CGRP or cells binding IB4 are nociceptive and that Mrgs and their co-expression with other markers of nocicep-
non-nociceptive cells do not label with these markers (Lawson tive neurons (Zylka et al 2003).
et al 1997, 2002; Gerke and Plenderleith 2001).
A group of mas-related genes (Mrgs) have been discov-
Coupling between C-Fiber Nociceptors
ered that are selectively expressed in small DRG neurons and
encode G proteincoupled receptors (GPCRs) (Dong et al Activation of one ber by action potential activity in
2001). Independently, sensory neuronspecic GPCRs (so- another is referred to as coupling. Coupling of action
called sensory neuronspecic receptors [SNSRs]) in which potential activity occurs between C bers in the normal

Stratum corneum
Signaling receptors
Epidermal free Stratum Cellular
nerve endings granulosum


Stratum spinosum


Stratum basalis P2X3

membrane TRPV1


Keratinocytes Peptidergic fibers

Figure 1-4. Schematic illustration of unmyelinated ber terminations in the epidermis. Non-peptidergic, MrgD+ neurons terminate as free nerve end-
ings in the most supercial layers of the epidermis. Peptidergic neurons terminate in deep layers of the epidermis. Some of the signaling receptors found on kera-
tinocytes and free nerve endings are also illustrated. (Artwork by Ian Suk, Johns Hopkins University; adapted from Dussor G, Koerber HR, Oaklander AL,
et al 2009 Nucleotide signaling and cutaneous mechanisms of pain transduction. Brain Research Reviews 60:2435.)

peripheral nerve of the monkey (Meyer et al 1985a). Cou- axons emerge from the supercial dermal nerve plexuses run-
pling frequently involves conventional CMHs. Coupling is ning beneath the epidermis. Schwann cells encase the axons
eliminated by injecting small amounts of local anesthetic at at the dermal level, but as the axons rise into the epidermis
the receptive eld of the CMH, thus indicating that the site between keratinocytes, the Schwann cell encasements are
of coupling is near the receptor. Collision studies indicate lost (Kruger et al 1981). Both clear round and large dense-
that the coupling is bidirectional. Sympathetic bers do not core vesicles are noted at the epidermal penetration site. The
appear to be involved in this coupling as demonstrated by vesicles are similar morphologically to vesicles present in
experiments in which the sympathetic chain is stimulated or other cells involved in hormone and neurotransmitter secre-
ablated (Meyer and Campbell 1987). The role of coupling tion. It is presumed that these vesicles secrete their contents
is unknown but it may relate to the are response or other into tissues on activation (see the efferent role of nociceptors
efferent functions of nociceptors (see below). Coupling below). Some of these bers appear to innervate Langerhans
between peripheral nerve bers is also one of the patho- cells. In small-ber neuropathies in which patients have pain
logical changes associated with nerve injury (e.g., Blumberg and decits in cutaneous pain sensibility, these axonal ter-
and Jnig 1982, Meyer et al 1985b). In this case, coupling minals stained by PGP 9.5 are markedly decreased (Holland
occurs at the site of axotomy. et al 1998).
As illustrated in Figure 1-4, free nerve endings can be traced
Anatomical Studies of Cutaneous far into the epidermal layer. These free nerve endings are
probably sensory and serve the sensations of pain, tempera-
ture, and itch. The parent axons of these unmyelinated termi-
Immunostaining for protein gene product (PGP) 9.5, a nals are probably both myelinated and unmyelinated. Some
carboxy-terminal ubiquitin hydrolase, has proved particu- of these free nerve endings are peptidergic and contain SP or
larly sensitive in identifying small-diameter afferents in the CGRP (Gibbons et al 1987). Others are non-peptidergic and
skin (Hsieh et al 1996). Vertical sections reveal that epidermal reach into the supercial layers of the epidermis.
8 Section One | Neurobiology of Pain

RELATIONSHIP OF NOCICEPTOR ACTIVITY (Torebjrk and Ochoa 1980), (2) the heat threshold for acti-
TO ACUTE PAIN SENSATIONS vation of CMHs recorded in awake humans is just below the
pain threshold (Van Hees and Gybels 1981), and (3) a linear
Nociceptors and Pain in Response relationship exists between responses of CMHs recorded in
to Heat Stimuli awake humans and ratings of pain over the temperature range
CMHs Signal Pain from Heat Stimuli 3951C (Torebjrk et al 1984).
to Glabrous Skin
We now examine the evidence that CMHs signal pain. In Correlations between Psychophysical
glabrous skin of the hand, two types of bers, CMHs (not Measures of the Heat Pain Threshold
AMHs) and warm bers, respond to short-duration heat stim- and Neurophysiological Results
uli (5 seconds) at temperatures near the pain threshold in We noted above that the heat threshold of CMHs is depen-
humans (i.e., around 45C). It is of interest, therefore, to com- dent on temperature at the level of the receptor and is inde-
pare how warm bers and CMHs encode information about pendent of the rate of change in temperature. At the same
noxious heat stimuli. Warm bers respond vigorously to gen- time when threshold temperature is measured at the surface of
tle warming of the skin and are thought to signal the sensation skin, CMHs have a lower threshold when the rate of increase
of warmth (Johnson et al 1979). An example of the response in temperature is slow. As discussed earlier, the reason for this
of a warm ber to stimuli in the noxious heat range is shown relates to thermal inertia.
in Figure 1-1B. The response of warm bers is not monotonic Human pain thresholds are sometimes measured as the
over this temperature range. In the example shown in Figure temperature that corresponds to the rst report of pain as
1-1B, the total response evoked at 49C was less than that at skin temperature is increased linearly (Marstock technique).
45C. Psychophysical studies in humans demonstrate that pain Investigators have noted that faster rates of change in tem-
increases monotonically with stimulus intensities between 40 perature lead to lower estimates of the heat pain threshold
and 50C. Because the responses of CMHs increase monotoni- (Yarnitsky and Ochoa 1990, Tillman et al 1995a). This is the
cally over this temperature range (Fig. 1-1A) and the responses opposite of the situation with the surface temperature thresh-
of warm bers do not (Fig. 1-1B), it follows that CMHs prob- old of CMHs but ts with the nding that suprathreshold
ably signal the sensation of heat pain to the glabrous skin of responses of CMHs vary directly with the rate of increase in
the hand (LaMotte and Campbell 1978).
Other evidence in support of a role for CMHs in pain
sensation includes the following: (1) human judgments of 2.0
pain in response to stimuli over the range of 4149C cor-
relate well with the activity of CMH nociceptors over this
range (Fig. 1-5, Meyer and Campbell 1981b); (2) selective
A-ber ischemic blocks or C-ber (local anesthetic) blocks
indicate that C-ber function is necessary for perception of
thermal pain near the pain threshold (Torebjrk and Hallin
Normalized response

1973); (3) the stimulus interaction effects observed in psy-

chophysical experiments (LaMotte and Campbell 1978) are
also observed in recordings from CMHs (Fig. 1-1A); (4) 1.0
Human subjects
the latency to pain sensation on glabrous skin following (n=12)
stepped changes in temperature is long and consistent with
input from CMHs (Campbell and LaMotte 1983); and (5)
in patients with congenital insensitivity to pain, microscopic
examination of peripheral nerves indicates an absence of CMHs
C bers (Bischoff 1979). (n=15)

Human Microneurographic Recordings

Microneurography has been used to record from nociceptive 0
41 43 45 47 49
afferents in awake humans and allows correlations between
the discharge of afferents and the reported sensations of the Stimulus temperature (C)
subject. The technique involves percutaneous insertion of a
Figure 1-5. Correlation of the response of C-ber nociceptors in the
microelectrode into fascicles of nerves such as the supercial monkey with pain ratings in human subjects. The close match between
radial nerve at the wrist. These studies have demonstrated the curves supports a role for C-ber nociceptors in heat pain sensation from
that the properties of nociceptors in humans and monkeys glabrous skin. The rst stimulus of the heat sequence was always 45C. The
are similar. In some experiments the microelectrode is also remaining nine stimuli ranged from 4149C in 1C increments and were
used to stimulate an identied, single nerve ber in awake presented in random order. Human judgments of pain were measured with a
magnitude estimation technique: subjects assigned an arbitrary number (the
human subjects to evoke specic sensations. Some, however, modulus) to the magnitude of pain evoked by the rst 45C stimulus and
argue that the size of the stimulating electrode is too large to judged the painfulness of all subsequent stimuli as a ratio of this modulus.
stimulate individual units (Wall and McMahon 1985). Given The response to a given stimulus was normalized by dividing by the modulus
this reservation, the following evidence from microneuro- for each human subject or by the average response to the rst 45C stimu-
lus for the C-ber mechano-heatsensitive nociceptors (CMHs). (Originally
graphic studies in humans points to the capacity of CMH published in Meyer RA, Campbell JN 1981 Peripheral neural coding of
activity to evoke pain: (1) intraneural electrical stimulation pain sensation. Johns Hopkins APL Technical Digest 2:164171. Copyright
of presumed single identied CMHs in humans elicits pain 1981 AAAS.)

temperature. Thus it is unlikely that the threshold responses contribute to the pain during a sustained, high-intensity heat
of CMHs are responsible for the heat pain thresholds. Rather, stimulus (Meyer and Campbell 1981a).
it appears that nociceptors must reach a certain discharge fre- In hairy skin, stepped heat stimuli evoke a double pain
quency (about 0.5 impulses/sec) for pain to be perceived (Van sensation (Lewis and Pochin 1937). The rst perception is a
Hees 1976, Yarnitsky et al 1992, Tillman et al 1995a). sharp pricking sensation, and the second sensation is a burn-
ing feeling that occurs after a momentary lull during which
A-Fiber Nociceptors and Heat Pain little if anything is felt. Myelinated afferent bers must
As shown in Figure 1-6, a long-duration heat stimulus applied signal the rst pain since the latency of response to the
to the glabrous skin of the hand in human subjects evokes rst pain is too small to be carried by C bers (Campbell
substantial pain for the duration of the stimulus. CMHs and LaMotte 1983). Type II A-ber nociceptors (see Fig.
exhibit a prominent discharge during the early phase of the 1-3) are ideally suited to signal this rst pain sensation:
stimulus, but this response adapts within seconds to a low (1) the thermal threshold is near the threshold temperature for
level. In contrast, type I AMHs are initially unresponsive but the rst pain (Dubner et al 1977), (2) the receptor utilization
then discharge vigorously. Therefore, type I AMHs probably time (time between onset of the stimulus and activation of the
receptor) is short (Treede et al 1998), and (3) the burst of
activity at the onset of the heat stimulus is consistent with the
perception of a momentary pricking sensation. The absence of a
Human ratings
rst pain sensation to heat stimuli applied to the glabrous skin of
30 the human hand correlates with the failure to nd type II A-ber
nociceptors on the glabrous skin of the hand in the monkey.
Scale used for pain

The preceding discussion indicates that nociceptors may sig-

intensity ratings

20 nal pain in response to heat stimuli. However, two caveats are

in order: (1) This does not mean that activity in nociceptors
always signals pain. It is clear that low-level discharge rates in
10 nociceptors do not always lead to sensation (e.g., Van Hees
and Gybels 1981, Cervero et al 1993). Central mechanisms,
including attentional and emotional states, quite obviously play
0 a crucial role in whether and how much nociceptor activity
leads to the perception of pain. (2) It is probable that receptors
CMHs other than nociceptors signal pain in certain circumstances. For
B 12
example, the pain in response to light touch that occurs after
10 certain nerve injuries or with tissue injury appears to be signaled
8 by activity in low-threshold mechanoreceptors (see below).

Nociceptors and Pain in Response
4 to Controlled Mechanical Stimuli
A-Fiber Nociceptors Signal Sharp Pain
0 A-ber and C-ber MSAs respond well to punctate mechani-
cal stimuli. When a controlled-force stimulus is applied to
AMHs (type I) the receptive eld, the response is greatest at the onset of the
C 30
stimulus and then slowly adapts. Like heat, repeated presen-
tations of a mechanical stimulus lead to pronounced fatigue.
A-ber nociceptors recover faster from fatigue than do C-ber

nociceptors (Fig. 1-7).

Much has been learned about the features of a mechani-
10 cal stimulus that determine the response of nociceptors to
mechanical stimuli. The discharge of nociceptors increases
with increased force and pressure, but these functions vary
0 depending on probe size: the smaller the probe, the greater
0 5 10 15 20 25 30 the response (Garell et al 1996). For cylindrical probes of dif-
Time from onset of stimulus (s) ferent diameter, the discharges are comparable if the intensity
of the stimulus is calculated according to force per length of
Figure 1-6. Ratings of pain by human subjects during a long-duration, the perimeter of the cylindrical probe. This suggests that the
intense heat stimulus (53C, 30 seconds) applied to the glabrous skin of stress/strain maximum that occurs at the edge of the cylindri-
the hand compared with responses of C-ber mechano-heatsensitive
nociceptors (CMHs) and type I A-ber mechano-heatsensitive noci- cal stimulus is the critical parameter for excitation of nocicep-
ceptors (AMHs). A, Pain was intense throughout the stimulus. B, The brisk tor terminals.
response of CMHs at the beginning of the stimulus changed to a low rate For a given probe size, the response of A-ber nociceptors
of discharge after 5 seconds. C, The response of AMHs increased during increases monotonically with force, whereas the response of
the rst 5 seconds and remained high throughout the stimulus. (Reprinted
with permission from Meyer RA, Campbell JN 1981 Myelinated nociceptive
C-ber nociceptors becomes saturated at higher force levels
afferents account for the hyperalgesia that follows a burn to the hand. Science (Fig. 1-8A; Slugg et al 2000). In general, the discharge in
213:15271529.) A bers is greater than that in C bers.
10 Section One | Neurobiology of Pain

1.2 A A-fibers

Evoked response (AP)

1.0 40

* 30
Normalized response

* *
* 10

8 16 32 64 128 256 512

0.2 Force (mN)

A-fiber nociceptors
C-fiber nociceptors B
100 Before A-fibers block
0 During A-fibers block

Normalized pain rating

15 30 60 150 300
Time between stimuli (s)

Figure 1-7. A-ber nociceptors recover faster from fatigue than do 60

C-ber nociceptors. Mechanical stimuli were presented to the receptive eld
of A-ber and C-ber nociceptors at different interstimulus intervals (with 10 40
minutes between stimulus pairs). The A-ber response (triangles) recovered
within 60 seconds, whereas the C-ber response (circles) took more than 150
seconds to recover. To normalize the data, the response to the test stimu- 20
lus was divided by the response to the immediately preceding conditioning
stimulus. (Adapted from Slugg RM, Meyer RA, Campbell JN 2000 Response
of cutaneous A- and C-ber nociceptors in the monkey to controlled-force 0
stimuli. Journal of Neurophysiology 83:21792191.) 8 16 32 64 128 256 512
Stimulus force (mN)
The area of the receptive eld that responds to mechani-
cal stimuli also responds to heat stimuli (Treede et al 1990). Figure 1-8. Comparison of responses of nociceptors to mechanical
stimuli in the monkey with pain ratings in human subjects. These data
However, the transducer elements that account for mechano- provide evidence that A-ber nociceptors signal the pain reported from sharp
sensitivity are probably different from those responsible for probes. A, Average responses of A-ber nociceptors (triangles) and C-ber
heat. For example, the heat response of nociceptors is readily nociceptors (circles) to controlled-force stimuli. The A bers exhibited a
sensitized by a heat injury, whereas the mechanical response monotonically increasing response, whereas the response of the C bers
reached a plateau at the higher force levels (0.4-mm-diameter cylindrical
is not (see below). probes; the total response to a stimulus 3 seconds in duration is plotted).
A-ber nociceptors appear to be responsible for the sharp B, Average pain ratings in response to controlled-force stimuli (open circle)
pain reported in response to punctate mechanical stimuli: increased monotonically in a manner comparable to that observed for the
(1) the reaction time to perception of pain is short, (2) the A-ber nociceptors. Selective block of A-ber function led to a signicant
decrease in pain ratings (lled circles). All pain ratings for a given subject
stimulusresponse function of A-ber nociceptors (Fig. 1-8A) were normalized by dividing by that subjects average rating of the maximum
is comparable to the pain ratings of human subjects (Fig. stimulus (0.2-mm-diameter cylindrical probes, stimulus duration of 1 second).
1-8B) over a similar force range, and (3) the pain in response (A, Adapted from Slugg RM, Meyer RA, Campbell JN 2000 Response of
to sharp probes is dramatically reduced during selective cutaneous A- and C-ber nociceptors in the monkey to controlled-force stim-
blockade of A-ber function (Fig. 1-8B; Magerl et al 2001). uli. Journal of Neurophysiology 83:21792191; B, adapted from Magerl W,
Fuchs PN, Meyer RA, et al 2001 Roles of capsaicin-insensitive nociceptors
Pretreatment of the skin with capsaicin abolishes heat pain in cutaneous pain and secondary hyperalgesia. Brain 124:17541764.)
sensitivity but does not greatly affect mechanical pain (Magerl
et al 2001). This suggests that the A-bers involved in sharp
pain are capsaicin insensitive; they could be type I AMHs or with a tonic stimulus persists through selective A-ber blockade
HTMs. (Andrew and Greenspan 1999b). Thus it appears that C-ber
MIAs signal the pain associated with tonic pressure.
C-Fiber MIAs Signal Pain in Response to Tonic
Nociceptors and Cold Pain Sensation
When long-duration mechanical stimuli are applied to human
subjects, the pain increases throughout the stimulus (Adriaensen Cold pain differs from heat pain in a number of important fac-
et al 1984). However, the response of MSAs to long-duration tors: (1) the cold pain threshold (14C on hairy skin; Harrison
suprathreshold stimuli adapts with time. Although C-ber and Davis 1999) is much farther from resting skin temperature
MIAs are, by denition, normally insensitive to mechanical (33C) than the heat pain threshold (about 45C), (2) the slope
stimuli, they develop a response to prolonged mechanical stim- of the stimulusresponse function is much steeper for heat pain
ulation (Schmidt et al 2000). In addition, the pain associated than for cold pain (Morin and Bushnell 1998), and (3) the lag

in response between stimulus onset and pain report suggests selective blockade of myelinated bers. Although C-ber MIAs
that cold pain is subserved by deeper receptors whereas heat do not respond to cowhage, QC bers and A-ber nociceptors
pain seems to be subserved by supercial receptors. Klement respond vigorously to cowhage (Ringkamp et al 2011). The
and Arndt (1992) demonstrated that cold pain could be evoked active ingredient in cowhage is the cysteine protease mucunain,
by cold stimuli applied within the veins of human subjects. which activates nociceptive terminals via protease-activated
A local anesthetic applied within the vein, but not in the overly- receptor 2 (PAR-2) and PAR-4 (Reddy et al 2008).
ing skin, abolished cold pain sensibility. It is therefore possible
that cold pain is served, at least in part, by vascular receptors. HYPERALGESIA: ROLE OF NOCICEPTORS
Just as the sensation of warmth is served by a specic set
of primary afferents (predominantly C bers), the sense of
cooling is served by a specic set of primary afferents (i.e., To understand the peripheral neural mechanisms of pain
cold bers). Cold bers are predominantly of the A type. induced by noxious stimuli is to understand only one aspect
They exhibit ongoing activity at room temperature, and their of pain sensibility. There is, in fact, a dynamic plasticity that
response increases markedly with gentle cooling. Stimuli that relates stimulus intensity and sensation. Of great biological
induce cold pain are not encoded well by these cold bers. importance in this regard is the phenomenon of hyperalgesia.
Although the majority of nociceptors have some response to Hyperalgesia is dened as a leftward shift of the stimulus
ice stimuli applied to the skin, Simone and Kajander (1997) response function that relates the magnitude of pain to stimu-
showed that all A-ber nociceptors respond to cold stimuli lus intensity. An example of this is seen in Figure 1-9A, which
below 0C. C-ber nociceptors may play a role in signaling shows human judgments of pain induced by heat stimuli before
cold pain sensation as well (LaMotte and Thalhammer 1982). and after a burn. It is evident that the threshold for pain is low-
A non-selective cation channel has been identied (called ered and pain in response to suprathreshold stimuli is enhanced.
ANKTM1 or transient receptor potential ankyrin 1 [TRPA1]) Hyperalgesia is a consistent feature of somatic and visceral
that has an activation threshold (17.5C) comparable to the tissue injury and inammation. Pharyngitis is associated with
cold pain threshold (Story et al 2003). This channel is found hyperalgesia in pharyngeal tissues such that merely swallow-
in a subset of nociceptive sensory neurons that are responsive ing induces pain. Micturition in the presence of a urinary tract
to intense heat and capsaicin. However, the role of TRPA1 in infection is painful, again reecting the presence of hyperal-
mediating noxious cold is still debated. gesia. In arthritis, slight motion of the joint results in pain.
A sunburn leads to pain with light touch and gentle heating.
Nociceptors and Chemically Evoked The peripheral neural mechanisms of hyperalgesia have been
studied in various tissues, including the joints, cornea, testicle,
gastrointestinal tract, and bladder. Much of the theoretical
Many chemical agents produce pain when applied to the skin. work on hyperalgesia, however, has evolved from studies of
In many cases the pain from these agents probably results the skin, and it is this work that will receive attention here.
from tissue injury and is therefore indirect. (Chemical media- Hyperalgesia occurs not only at the site of injury but also
tors associated with inammation are described later.) One in the surrounding uninjured area. Hyperalgesia at the site of
exception that has received a lot of attention is capsaicin. injury is termed primary hyperalgesia, whereas hyperalgesia in
Intradermal injection of capsaicin produces intense burning the uninjured skin surrounding the injury is termed secondary
pain that lasts for several minutes. When capsaicin is injected hyperalgesia (Lewis 1935). Hyperalgesia exemplies the func-
into the receptive eld of C-ber MSAs, the response is weak tional plasticity of the nervous system. As we will see, the neu-
(relative to the heat response) and of short duration (Baumann ral mechanisms for primary and secondary hyperalgesia differ.
et al 1991). In contrast, A-ber and C-ber MIAs exhibit a In discussing hyperalgesia, it is useful to consider the fol-
long-lasting, vigorous response to capsaicin (Schmelz et al lowing variables: (1) energy form of the injury, (2) type of
2000b, Ringkamp et al 2001), thus suggesting that these bers tissue involved, (3) energy form of the test stimulus, and (4)
are responsible for the pain induced by capsaicin. The pun- location of the testing relative to the area injured. These vari-
gent effects of capsaicin appear to be mediated by the TRPV1 ables interact in complex ways. For example, it will be shown
receptor expressed on nociceptive bers. This receptor appears that nociceptors will become sensitized to mechanical stimuli
to be activated by heat and protons (acid) as well. (the energy form of the test stimulus), but only after certain
Another chemical of interest is histamine, which produces forms of injury (i.e., injection of inammatory mediators).
a long-lasting itch when applied to the skin. Injection of his- An experimental design frequently used for study of the
tamine into the receptive eld of C-ber MSAs leads to a last- neural mechanisms of hyperalgesia is to characterize the
ing response (Johanek et al 2008). Iontophoresis of histamine response properties of a given ber, then apply a manipula-
into the receptive eld of a subpopulation of C-ber MIAs tion that under usual circumstances would produce hyperal-
also produces a vigorous, long-lasting response (Schmelz et al gesia, and nally assess whether this manipulation has altered
1997), which suggests that both CMHs and C-ber MIAs the response properties of the ber in question. Cutaneous
may play a role in histamine-induced itch. Histamine prob- hyperalgesia has been studied after thermal injury (burn or
ably activates nociceptors via the H1 receptor located on freeze lesions), after local administration of chemicals (e.g.,
peripheral terminals. capsaicin, mustard oil, or menthol), after a mechanical injury
Because cowhage spicules produce an intense itch that is not to the skin (e.g., incision, crushing), and after exposure to
blocked by topical antihistamines (Johanek et al 2008), and they ultraviolet radiation. The main features of the hyperalgesia
provide a useful tool to investigate the chronic itch in patients that develops after these various injuries are quite similar.
that is resistant to antihistamine treatment. In about half of nor- As shown in Figure 1-10, the relative locations of the injury
mal subjects, cowhage-induced itch is greatly attenuated during site, the test site, and the receptive eld of the sensory neuron
12 Section One | Neurobiology of Pain

A 8.0 B AMHs
7.0 After


Normalized neuronal response

Normalized pain rating

41 43 45 47 49
Stimulus temperature (C)


C 2.0 CMHs
2.0 Human ratings

1.0 Before
0 0
41 43 45 47 49 41 43 45 47 49
Stimulus temperature (C) Stimulus temperature (C)

Figure 1-9. Hyperalgesia and nociceptor sensitization after a cutaneous burn injury. Responses to heat stimuli were obtained 5 minutes before and
10 minutes after a 53C, 30-second burn on the glabrous skin of the hand. The burn resulted in increases in the magnitude of pain (hyperalgesia) in human
subjects that were matched by enhanced responses (sensitization) in type I A-ber mechano-heatsensitive nociceptors (AMHs) in the monkey. In contrast,
C-ber mechano-heatsensitive nociceptors (CMHs) exhibited decreased sensitivity after the burn. A, Human judgments of pain. B, Responses of type I AMHs
in the monkey. C, Responses of CMHs in the monkey. The same type of random heat sequence and normalization described in Figure 1-5 was used. Because
the AMHs did not respond to the 45C stimulus before the burn, the AMH data were normalized by dividing by the response to the rst 45C stimulus after
the burn. (Reprinted with permission from Meyer RA, Campbell JN 1981 Myelinated nociceptive afferents account for the hyperalgesia that follows a burn
to the hand. Science 213:15271529.)

being studied dictate whether the experiment provides infor- of the hand, marked hyperalgesia to heat develops as shown in
mation regarding the mechanisms of primary or secondary Figure 1-9A (Meyer and Campbell 1981a). The hyperalgesia
hyperalgesia (Treede et al 1992). These three variables may is manifested as a leftward shift of the stimulusresponse func-
interact in any of six ways. As shown in Figure 1-10, when tion that relates the magnitude of pain to stimulus intensity.
the injury and the test site coincide (Fig. 1-10A and B), the For example, the 41C stimulus was not painful before the
study has provided a basis by which to consider the mecha- burn but after the injury was as painful as the 49C stimulus
nism of primary hyperalgesia, whereas when the test site and before the injury.
the injury site diverge (Fig. 1-10CF), the study has provided
a basis by which to account for secondary hyperalgesia. Peripheral Sensitization as a
When the paradigms shown in Figure 1-10A and B are Mechanism for Primary Hyperalgesia
used, it is found that under certain circumstances, nocicep-
to Heat Stimuli
tors exhibit an increased response to the test stimulus. Thus,
peripheral neural mechanisms are likely to account for at least Substantial evidence favors the concept that the primary
some aspects of primary hyperalgesia. In contrast, primary hyperalgesia to heat stimuli that develops at the site of a burn
afferent nociceptors do not develop an enhanced response to injury is mediated by sensitization of nociceptors (Meyer and
the test stimulus when the paradigms shown in Figure 1-10CF Campbell 1981a, LaMotte et al 1982). Sensitization is dened
are investigated. By default, therefore, the mechanism for sec- as a leftward shift of the stimulusresponse function that
ondary hyperalgesia must reside within the CNS. relates the magnitude of the neural response to stimulus inten-
sity. Sensitization is characterized by a decrease in threshold,
an augmented response to suprathreshold stimuli, and ongo-
PRIMARY HYPERALGESIA ing spontaneous activity. These properties correspond to the
Hyperalgesia to Heat Stimuli properties of hyperalgesia (Table 1-2).
To explain the hyperalgesia that occurs with a burn on
We rst consider the situation in which a burn injury is applied the glabrous skin of the hand, a correlative analysis of sub-
to the skin and the test stimulus is heat applied to the location jective ratings of pain in humans with responses of nocicep-
of the burn injury. When a burn is applied to the glabrous skin tors (CMHs and type I AMHs) in anesthetized monkeys was

Primary hyperalgesia A Before injection

(injury and test site coincide)
5 bar
A Injury within RF B Injury outside RF

5 0 5 10 15 20
Time (s)

B Chemical injection
Secondary hyperalgesia 7

(injury and test site do not coincide) 6


17 bar
Injury within RF Injury outside RF 5
7 5 3 1 3 1 5 7 9
Time (min)
C 30 min after injection
5 bar

5 0 5 10 15 20

Injury site Original RF Time (s)

Test site Expanded RF Figure 1-11. Example of sensitization to mechanical stimuli for an
A-ber nociceptor following a chemical injection. A, The ber did not
respond to the application of a 5-bar stimulus for 15 seconds to the most
sensitive area within its receptive eld. The initial mechanical threshold for
Figure 1-10. Experimental congurations for testing the neural mech- this ber was 10 bar, and therefore it was a mechanically insensitive afferent
anisms of primary and secondary hyperalgesia. To study primary hyper- (MIA). B, This MIA responded vigorously to a 10-L intradermal injection of
algesia, the site of injury (indicated by lled circles) and the site of testing a chemical mixture containing 10 nmol bradykinin, 0.3 nmol prostaglandin
(indicated by the Xs) must coincide. Alterations in the stimulusresponse E1, 30 nmol serotonin, and 30 nmol histamine. (Each asterisk indicates the
function from stimuli applied to the original receptive eld (RF) (A) and time of needle insertion; bin size = 5 seconds). C, Sensitization to mechanical
expansion of the RF toward the injury site (B) are substrates for primary stimuli was demonstrated in this ber 30 minutes after chemical injection.
hyperalgesia. To study secondary hyperalgesia, the site of injury and the site The ber now responded to application of the 5-bar stimulus. Each vertical
of testing must not coincide (C and D). Sensitization of the stimulusresponse tic corresponds to the time of occurrence of an action potential. The von Frey
function as revealed by testing within the original RF may occur following threshold decreased (from 10 to 4 bar), and the receptive eld area increased
injuries within (C) or outside the RF (D). Expansion of the RF to include a (from 9 to 88 mm2). No response to heat was observed either before or after
test site outside the original RF may occur for injuries within (E) or outside the injection. (Reproduced with permission from Davis KD, Meyer RA,
(D) the RF. (Reprinted from Treede RD, Meyer RA, Raja SN, et al 1992 Campbell JN 1993 Chemosensitivity and sensitization of nociceptive affer-
Peripheral and central mechanisms of cutaneous hyperalgesia. Progress in ents that innervate the hairy skin of monkey. Journal of Neurophysiology
Neurobiology 38:397421. Copyright 1992, with permission from Elsevier.) 69:10711081.)

Table 1-2 Comparison of Characteristics Sensitization is not a uniform property of nociceptors. Tissue
of Hyperalgesia and Sensitization type and the nature of the injury are important variables. For
example, CMHs that innervate hairy skin become sensitized,
RESPONSE) RESPONSE) whereas as described above, CMHs that innervate the glabrous
skin of the hand do not become sensitized to a burn injury
Decreased pain threshold Decreased threshold for response
(Campbell and Meyer 1983). Thus, CMHs appear to play a
Increased pain in response to Increased response to role in accounting for hyperalgesia to heat stimuli on hairy skin
suprathreshold stimuli suprathreshold stimuli (LaMotte et al 1983). These data support the conclusion that
Spontaneous pain Spontaneous activity the hyperalgesia to heat stimuli that occurs at the site of an
injury is due to sensitization of primary afferent nociceptors.

performed (Meyer and Campbell 1981a). Test heat stimuli Hyperalgesia to Mechanical Stimuli
were applied to the glabrous skin of the hand before and after
a 53C, 30-second burn. The burn led to prominent hyperal- Distinguishing hyperalgesia to mechanical stimuli in the pri-
gesia in the human subjects (Fig. 1-9A). The CMHs showed mary and secondary zones may be incorrect in some respects
a decreased response following the burn (Fig. 1-9C), whereas since the mechanism for hyperalgesia in the two zones may
the type I AMHs were markedly sensitized (Fig. 1-9B). Thus, have some common elements. The mechanisms discussed in
it is likely that for thermal injuries on the glabrous skin of the this section, however, will be limited to those applicable to
hand, AMHs, not CMHs, code for the heat hyperalgesia. the primary zone.
14 Section One | Neurobiology of Pain

Different forms of mechanical hyperalgesia have been char- Loss of Central Inhibition as a
acterized. One form is evident when the skin is gently stroked Mechanism of Mechanical Hyperalgesia
with a cotton swab and is referred to as stroking hyperal- in the Primary Zone
gesia, dynamic hyperalgesia, or allodynia. The second
form of hyperalgesia is evident when punctate stimuli, such Under usual circumstances, production of pain from activa-
as von Frey probes, are applied and, accordingly, has been tion of nociceptors with mechanical stimuli is inhibited in the
termed punctate hyperalgesia. Hyperalgesia to tonic stim- CNS by the concurrent activation of low-threshold mechano-
ulation with a blunt probe, called pressure hyperalgesia, receptors (e.g., Bini et al 1984). There is evidence that injury
and impact hyperalgesia to shooting small bullets against the decreases the responsiveness of low-threshold mechanorecep-
skin at a controlled velocity have also been described in the tors. Hyperalgesia to mechanical stimuli in the primary zone
primary hyperalgesic zone (Kilo et al 1994). As discussed in could therefore be due to injury to low-threshold mechanore-
the later section on secondary hyperalgesia, the mechanism ceptors, which would lead to central disinhibition of nocicep-
for these different forms of mechanical hyperalgesia is prob- tor input and thus result in enhanced pain (i.e., hyperalgesia).
ably different. Stroking hyperalgesia is thought to be signaled
by low-threshold mechanoreceptors, whereas punctate hyper- INFLAMMATORY MEDIATORS
algesia is mediated at least in part by nociceptors. Pressure AND NOCICEPTORS
hyperalgesia and impact hyperalgesia are probably mediated
by sensitized C bers. Another form of mechanical hyperalge- Injury results in the local release of numerous chemicals from
sia termed progressive tactile hypersensitivity, which may non-neuronal cells (e.g., broblasts, mast cells, neutrophils,
contribute to the allodynia associated with inammation, has monocytes, and platelets), as well as from the sensory termi-
been described (Ma and Woolf 1997). nals of primary afferent bers that mediate or facilitate the
inammatory process. Inammatory mediators include pros-
Nociceptor Sensitization as taglandins, leukotrienes, bradykinin, serotonin, histamine,
a Mechanism for Mechanical SP, thromboxanes, platelet-activating factor, purines such as
adenosine and ATP, protons, and free radicals (Fig. 1-12, see
Hyperalgesia in the Primary Zone
also Basbaum et al 2009). Cytokines, such as interleukins and
Primary hyperalgesia to mechanical stimuli appears to be due, tumor necrosis factor, and neurotrophins, especially NGF, are
at least in part, to sensitization of primary afferent nocicep- also generated during inammation. NGF not only is necessary
tors to mechanical stimuli. This sensitization is manifested in for the survival of nociceptors during development but may
several ways. also play an important role during inammatory processes in
adult animals. Some of these agents can directly activate noci-
Lowered Threshold ceptors, whereas others act indirectly via inammatory cells,
Thresholds to mechanical stimulation of either CMHs or which in turn release algogenic agents. Other mediators lead
AMHs recorded in primates or humans, as measured with von to sensitization of the nociceptor response to natural stimuli
Frey hairs (a punctate stimulus), are not changed by heat and/ and therefore play a role in primary hyperalgesia. The variety
or mechanical injury (e.g., Thalhammer and LaMotte 1982, of chemical mediators released during inammation can have
Campbell et al 1988a). However, MIAs have been shown a synergistic effect in potentiating nociceptor responses.
to develop mechanical sensitivity after inammation. Figure A variety of metabotropic and ionotropic receptors,
1-11 shows the response of an A-ber MIA to mechani- including purinergic and glutamatergic receptors, have been
cal stimuli before and after exposure to a mixture of algesic identied on DRG cells and on the peripheral terminals of
inammatory mediators (bradykinin, histamine, serotonin, nociceptive afferent bers. Activation of these receptors may
and prostaglandin E1 [PGE1]). This MIA was unresponsive modulate the sensitivity of peripheral nociceptors to exog-
to the 5-bar von Frey probe initially, but a robust response to enous stimuli (Carlton and Coggeshall 1998).
this probe developed after inammation.
Arachidonic Acid Metabolites
Increased Response to Suprathreshold Stimuli
Although inammation does not result in a reduction in The prostaglandins, thromboxanes, and leukotrienes are
the mechanical threshold of AMHs and CMHs, responses a large family of arachidonic acid metabolites collectively
to suprathreshold stimuli may be augmented (Cooper et al known as eicosanoids. The eicosanoids are generally consid-
1991). Inammation of the rat paw results in an enhanced ered to not activate nociceptors directly but rather enhance
response to suprathreshold mechanical stimuli, spontaneous the sensation of pain in response to natural stimuli and other
activity, and expanded receptor elds for both A- and C-ber endogenous chemicals by increasing the frequency of action
nociceptors (Andrew and Greenspan 1999a). potential ring (for reviews see Schaible et al 2002, Cunha
and Ferreira 2003, Momin and McNaughton 2009). A sen-
Expansion of the Receptive Field sitizing and direct excitatory effect of PGE2 and PGI2, how-
The receptive elds of AMH bers, as well as some CMH ever, has been demonstrated in afferents innervating joints.
bers, expand modestly into the area of an adjacent heat Prostaglandins are synthesized by the constitutive enzyme
(Thalhammer and LaMotte 1982) or mechanical (Reeh et al cyclooxygenase-1 (Cox-1) and by Cox-2, an enzyme induced
1987) injury. As a result of this expansion, heat or mechanical in peripheral tissues by inammation (Ballou et al 2000).
stimuli delivered after the injury will activate a greater num- Several prostaglandins, PGI2, PGE1, PGE2, and PGD2, are
ber of bers. This spatial summation would be expected to considered to play a role in inammatory pain and hyper-
induce more pain. algesia. Prostaglandins reduce the threshold for initiation

Platelets damage


TNF- Co l d
IL-6 Adenosine
Mast cell t


Endothelial Platelets
Endothelin K2P PKC


Schwann Nav Gene

cell regulation


Figure 1-12. Potential mediators of peripheral sensitization after inammation. Tissue injury and inammation lead to the release of numerous
chemicals from non-neuronal and neuronal cells, such as mast cells, macrophages, platelets, immune and endothelial cells, Schwann cells, keratinocytes,
broblasts, and peripheral nociceptor terminals. Mediators released include protons (H+), purines (adenosine, adenosine triphosphate), nerve growth factor
(NGF), cytokines such as tumor necrosis factor (TNF-) and interleukins (IL-1, IL-6), leukemia inhibitory factor (LIF), prostaglandin E2 (PGE2), bradykinin,
histamine, serotonin (5-HT), platelet activating factor (PAF), and endothelin. These mediators may act directly to alter the sensitivity of peripheral nocicep-
tors or indirectly via coupling to one or more peripheral membrane-bound receptors, including transient receptor potential (TRP) channels, acid-sensitive
ion channels (ASICs), purinergic (P2X) receptors, G proteincoupled receptors (GPCRs), two-pore potassium channels (K2P), and receptor tyrosine kinase
(RTK). Binding of the ligands to these receptors can initiate a cascade of events that includes activation of second-messenger systems (protein kinase A [PKA]
and C [PKC]) and alteration of gene regulation. (Artwork by Ian Suk, Johns Hopkins University; adapted from Woolf CJ, Costigan M 1999 Transcriptional
and posttranslational plasticity and the generation of inammatory pain. Proceedings of the National Academy of Sciences of the United States of America

of action potentials and increase the excitability of sensory (Levine et al 1984) and in sensitization to mechanical stimuli
neurons by decreasing the threshold for activation of a noci- (Martin et al 1987).
ceptor-specic voltage-activated Na current, Nav1.8, and
increasing intracellular cyclic adenosine monophosphate Bradykinin
(cAMP) levels (England et al 1996, Gold et al 1996). The
prostaglandin-induced increase in ring frequency may also Several lines of evidence suggest that bradykinin may also
result from an increase in the hyperpolarization-activated play a critical role in inammatory pain and hyperalgesia
current (Ih), which leads to faster depolarization toward (see Couture et al 2001, Meini and Maggi 2008 for reviews).
the action potential threshold, the consequence of which Bradykinin is released on tissue injury (e.g., from plasma),
is a decrease in the time interval between successive action is present in inammatory exudates, and excites and sensi-
potentials (Momin and McNaughton 2009). Of the leu- tizes unmyelinated and myelinated nociceptors to natural
kotrienes (metabolites of the lipoxygenase pathway), LTD4 stimuli (Beck and Handwerker 1974, Khan et al 1992).
and LTB4 have been suggested to play a role in hyperalgesia Administration of exogenous bradykinin produces pain and
16 Section One | Neurobiology of Pain

transient hyperalgesia to heat in humans (Manning et al nociceptors to bradykinin and heat (Mizumura et al 1995).
1991). Bradykinin acts on B1 and B2 receptors to induce Mechanosensitive cutaneous nociceptors in rats and humans
nociceptor sensitization by activation of phospholipase C respond only weakly to histamine (Lang et al 1990), but a
(PLC) and protein kinase C (PKC), production of arachi- subpopulation of mechano-insensitive C bers was vigorously
donic acids, and modulation of the TRPV1 channel (see the excited by histamine (Schmelz et al 1997). Activation of his-
section on the vanilloid receptor below) (Reeh and Sauer tamine H3 receptors, a ligand-gated ion channel that modu-
1997, Banik et al 2001). lates the inux of Na+, however, leads to decreased release
of inammatory peptides and reduced pain and inammation
(Cannon et al 2007).
The low pH levels found in inamed tissue have led to the Purines
hypothesis that local acidosis may contribute to the pain
and hyperalgesia associated with inammation. Continu- During inammation and tissue injury, purines such as ade-
ous administration of low-pH solutions in humans causes nosine and its mono- or polyphosphate derivatives (AMP,
pain and hyperalgesia to mechanical stimuli (Steen and Reeh ADP, ATP) may be released or leak into the extracellular
1993). This correlates with the observation that protons space and activate nociceptors (for review see Burnstock
selectively activate nociceptors and produce sensitization of 2009). Platelets are a rich source of ATP, and aggregation of
nociceptors to mechanical stimuli. Excitation of nociceptors platelets or lysis of cells can lead to release of ATP. Adeno-
by protons does not undergo tachyphylaxis or adaptation, sine and its phosphates have been reported to induce pain in
and a synergistic excitatory effect of protons and a combi- a human blister base. Intra-arterial or intradermal injection
nation of inammatory mediators has been reported (Steen of adenosine also causes pain, and intravenous/intracoronary
et al 1996). infusion of adenosine induces angina-like symptoms (Sylvn
A class of acid-sensing ion channels (ASICs), a subgroup of et al 1986). In animals, adenosine enhances the response to
the degenerin/epithelial sodium channel (DEG/ENaC) family formalin, presumably via the A2 receptor. Animals lacking the
of proteins, has emerged as sensors of low pH (see Holzer adenosine A2a receptor are hypoalgesic to heat stimuli (Ledent
2009, Sluka et al 2009 for review). ASICs signal moderate et al 1997).
decreases in extracellular pH, in contrast to TRPV1, which A number of lines of evidence support the potential role
is activated by severe acidosis (pH values below 6). ASIC1A of ATP as a peripheral mediator of pain. ATP is found at
and ASIC3 have been identied in DRG neurons, and their increased levels at sites of inammation and can activate
expression is increased by inammation, nerve injury, and nociceptors. Psychophysical studies in humans indicate that
bone cancer, thus suggesting that ASICs may play a role in iontophoresis of ATP into normal skin results in dose-related
mediating or modulating pain in these conditions. The obser- pain. ATP-induced pain is dependent on capsaicin-sensitive
vation that a non-selective ASIC inhibitor, amiloride, reduces neurons; repeated topical application of capsaicin reduces
cutaneous acid-evoked pain in humans suggests that ASICs the ATP-induced pain to 25% of normal. In addition, the
may be a potential therapeutic target for inammatory pain ATP-induced pain is increased two- to three-fold when ion-
(Ugawa et al 2002). tophoresed into skin made hyperalgesic by acute capsaicin
treatment or by ultraviolet inammation. Thus, in inamma-
tory conditions ATP may activate nociceptors and serve as an
endogenous mediator of pain (Hamilton et al 2000). In human
Mast cells, on degranulation, release platelet-activating microneurographic studies, injection of ATP activated 60% of
factor, which in turn leads to the release of serotonin mechano-responsive and mechano-insensitive C-nociceptive
(5-hydroxytryptamine [5-HT]) from platelets. Serotonin bers without sensitizing these bers to mechanical or heat
causes pain when applied to a human blister base (Richard- stimuli (Hilliges et al 2002).
son and Engel 1986) and can activate nociceptors (Lang et al Receptors for ATP have been found on primary sensory
1990). Serotonin can also potentiate the pain induced by bra- neurons both in the DRG and in the periphery. Multiple
dykinin and enhance the response of nociceptors to brady- purinergic (P2) receptors have been suggested to be involved
kinin. Additional evidence for a role of 5-HT in nociception in pain signaling and modulation. ATP presumably activates
stems from observations that 40% of lumbar DRG neurons, nociceptive neurons in normal skin via the P2X3 receptor
mostly small to medium-sized cells, are immunoreactive for and the heteromeric P2X2/P2X3 receptor (Chen et al 1995,
the 5-HT2A receptor and many of these cells also express the Lewis et al 1995, Cook et al 1997). Messenger RNA for
TRPV1 receptor (Van Steenwinckel et al 2009). most of the P2X receptors (16) has been found in DRG
neurons. In particular, both mRNA for the P2X3 receptor
and the receptor protein itself have been found in small-
diameter neurons in the DRG. Local intradermal injection of
Release of SP from nociceptor terminals can cause the release agents activating P2X receptors results in dose-related pain
of histamine from mast cells. Histamine can lead to a variety behavior in rodents that is mediated by capsaicin-sensitive
of responses, including vasodilatation and edema. The role of neurons (Bland-Ward and Humphrey 1997) and enhanced
histamine in pain sensation is less clear since application of pain behavior in response to formalin (Sawynok and Reid,
exogenous histamine to the skin produces itch and not pain 1997). The proportion of C-ber nociceptors responding
sensations (Simone et al 1991a). Histamine excites polymodal and the magnitude of their response are increased by P2X
visceral nociceptors, especially when applied in high concen- agonists in inamed skin. Activation of homomeric P2X3
trations (Koda et al 1996), and potentiates the responses of receptors is thought to contribute to acute nociception and

inammatory pain, whereas activation of heteromeric P2X2/3 glutamate receptors [iGluRs]) or through G proteincoupled
receptors appears to modulate the longer-lasting nociceptive metabotropic receptors (mGluRs). Based on sequence homol-
sensitivity associated with nerve injury or chronic inamma- ogy and physiological and pharmacological properties, the
tion (Burnstock 2009). mGluRs have been further divided into three groupsgroup
Recently, it has been suggested that peripheral adenosine I (mGluR 1 and 5), group II (mgluR 2 and 3), and group III
receptors may also be involved in the modulation of inam- (mGluR 4, 6, 7, and 8). iGluR, mGluR1, and mGluR5 recep-
matory pain. A1 adenosine receptors are expressed in DRG tors have been identied on unmyelinated axons in the skin
cells, and peripheral activation of these receptors results in a (Bhave et al 2001, Zhou et al 2001). About 40% of lumbar
reduction in inammatory hyperalgesia via interactions with DRG cells contain mGluR2/3 immunoreactivity, and a major-
the nitric oxide/cyclic guanosine monophosphate/protein ity of these cells are IB4+ small cells.
kinase G intracellular signaling pathways (Lima et al 2010). Several lines of evidence indicate a role of peripheral
mGluRs in nociception and inammatory pain. Peripheral
application of glutamate activates nociceptors, and periph-
eral administration of ligands binding to glutamate receptors
During inammation, cytokines (e.g., interleukin-1 [IL-1], induces pain behavior in animals. Involvement of periph-
tumor necrosis factor [TNF-], IL-6) are released by a vari- eral iGluR, mGluR1, and mGluR5 in formalin-induced pain
ety of cells (e.g., macrophages, Schwann cells) and regulate the behavior and glutamate-induced thermal hyperalgesia has
inammatory response (see Miller et al 2009, Schaible 2010). been demonstrated (Davidson et al 1997). Intraplantar, but
Clinical studies have shown that TNF- levels in synovial uid not intrathecal or intracerebroventricular administration of
are increased in painful joints (Shafer et al 1994). Treatment an mGluR5 antagonist reduced inammatory hyperalgesia.
with antibodies against TNF- has been reported to improve Neurons in the DRG can be double-labeled with antisera for
the symptoms accompanying rheumatoid arthritis, including mGluR5 and VR1, thus suggesting that mGluR5 is expressed
pain (Elliott et al 1994). Studies in animals have demonstrated on the peripheral terminals of nociceptive neurons and con-
mechanical and thermal hyperalgesia after systemic or local tributes to inammatory hyperalgesia (Walker et al 2001). In
injection of IL-1, IL-6, and TNF-. Additionally, treatment particular, mGluR1 activates PLC, which leads to release of
with antiserum against TNF- is able to inhibit or delay the Ca2+ from intracellular stores and activation of PKC.
onset of hyperalgesia in experimental models of inammation Endogenous sources of glutamate in the periphery include
(Woolf et al 1997). plasma, macrophages, epithelial and dendritic cells in the epi-
Cytokines may excite nociceptors either by rapid altera- dermis and dermis, and Schwann cells. In addition, periph-
tions in the properties of ion channels expressed in sensory eral processes of the primary afferents contain glutamate, and
neurons; indirectly by stimulating the release of other media- nociceptor stimulation can cause peripheral release of gluta-
tors such as prostaglandins, neurotrophins, and ATP; and by mate from the terminals of these afferents.
longer-term changes resulting from new gene transcription. Peripheral mGluRs are also considered to have antinoci-
Direct excitation and sensitization of nociceptive afferent ceptive effects. Peripheral administration of group II mGluR
bers to thermal and mechanical stimuli have been shown for agonists blocks PGE2-induced thermal hyperalgesia, and acti-
IL-1 and TNF- (Fukuoka et al 1994). When applied along vation of these receptors results in depression of the responses
a peripheral nerve, TNF- induces ectopic activity in nocicep- of nociceptors sensitized by exposure to formalin or inam-
tive afferent bers (Sorkin et al 1997). matory soup (Yang and Gereau 2002, Du 2008). These
IL-6 in combination with its soluble IL-6 receptor can observations suggest that selective group II agonists may be a
sensitize nociceptors to heat as evidenced by increased heat- therapeutic target for inammatory pain states.
evoked intradermal release of CGRP (Obreja et al 2002).
Other cytokines, IL-1 and TNF-, also produce transient Nerve Growth Factor
sensitization of heat-evoked release of CGRP from nocicep-
tors in rat skin (Opre and Kress 2000). IL-6decient mice NGF may contribute to inammatory pain via direct and indi-
show reduced mechanical and thermal hyperalgesia following rect mechanisms (for review see Pezet and McMahon 2006,
inammation (Xu et al 1997). These studies provide evidence Watson et al 2008). Pro-inammatory cytokines stimulate the
for a role of cytokines in inammation-associated hyperal- release of NGF from various sources, including broblasts,
gesia. The sensitization of nociceptors by cytokines may be keratinocytes, Schwann cells, and inammatory cells (lym-
mediated by p38-induced phosphorylation of TTX-resistant phocytes, macrophages, and mast cells). NGF stimulates mast
sodium channels, as well as by up-regulation of TRPV1 cells to release histamine and serotonin. NGF can also induce
expression and function (Jin and Gereau 2006; for review see heat hyperalgesia by acting directly on the peripheral termi-
Ma and Quirion 2007). nals of primary afferent bers (Chuang et al 2001). Transgenic
animals modied to overexpress NGF show hyperalgesic pain
behavior (Davis et al 1993a). NGF sensitizes nociceptors and
Excitatory Amino Acids
may alter the distribution of A bers such that a greater
A number of excitatory amino acids (EAAs) and peptide recep- proportion of bers have nociceptor properties (Stucky et al
tors are present at post-synaptic sites in the dorsal horn. These 1999). NGF has been implicated in the inammation-induced
receptors have been found on DRG cells and the presynaptic changes in nociceptor response properties, such as an increase
terminals of primary afferents and are considered to play a in the incidence of ongoing activity, increase in the maximum
role in the modulation of nociceptive impulses (see Carlton ber following frequency, and changes in the conguration
2001, Goudet et al 2009). The most studied EAA, glutamate, of the action potential of DRG neurons (Djourhi et al 2001).
can act either through ligand-gated ion channels (ionotropic The inammation-induced changes in nociceptive neurons are
18 Section One | Neurobiology of Pain

prevented by sequestration of NGF (Koltzenburg et al 1999). also appears to play an important role in inammatory
Cultured DRG neurons from inamed animals exhibit sponta- hyperalgesia (Rathee et al 2002, Distler et al 2003). Finally,
neous activity, and cultured DRG neurons from non-inamed some inammatory mediators activate TRPV1 indirectly via
animals exhibit spontaneous activity when cultivated for the production of fatty acid agonists (Shin et al 2002). For
1 day with NGF (Kasai and Mizumura 2001). These studies instance, bradykinin, acting at B2 receptors, excites cutaneous
suggest that in inamed rats NGF may play a role in inducing nociceptors via production of the 12-lipoxygenase metabolite
spontaneous activity in DRG neurons. of arachidonic acid 12-hydroperoxyeicosatetraenoic acid (12-
NGF modulates the activity of ligand- and voltage-gated HPETE), which in turn acts as a TRPV1 agonist.
ion channels involved in nociception, such as TRPV1,
P2X3, ASIC3, and Nav1.8. NGF potentiates responses of Endothelin Receptors
the TRPV1 receptor (see the section on the vanilloid recep- Endothelins are vasoactive peptides that are widely distrib-
tors), and NGF-induced hyperalgesia is absent in TRPV1 uted in somatic and visceral tissue (for reviews see Hans et al
knockout mice (Chuang et al 2001). NGF-induced hyperal- 2009, Khodorova et al 2009). Endothelin-1 (ET-1) is synthe-
gesia may be mediated via its actions on the TTX-resistant sized and released by endothelial cells, as well as by leuko-
sodium channel Nav1.8. NGF-induced thermal hyperalgesia cytes and macrophages, and acts via GPCRsETA and ETB.
failed to develop in mice with a mutation in the Nav1.8 gene ETA receptors are found in a large proportion of small cells in
(Kerr at al 2001). Binding of NGF to TrkA stimulates the DRGs. ETB receptors are expressed mainly in keratinocytes,
mitogen-activated protein kinase (MAPK), phosphatidyl-3- DRG satellite cells, and Schwann cells and may induce the
kinase (PI3K), and PLC- intracellular signal transduction synthesis and release of PGE2. Peripheral administration of
pathways (for details see Cheng and Ji 2008). Potential clini- ET-1 results in hyperalgesia that is attenuated by ETA antago-
cal therapeutic approaches being explored include human- nists. ET-1 also potentiates the effects of other algogens such
ized monoclonal antibodies to NGF or its tyrosine kinase as PGE2, capsaicin, and formalin. Activation of ETA recep-
receptor TrkA and sequestration of NGF via soluble recep- tors on neurons results in enhanced function of TRPV1 and
tor protein that binds NGF. TTX-resistant Na channels and an increase in intracellular
Ca2+ levels, which in turn activates PKC and other second-
messenger systems and leads to enhanced excitability of noci-
Other Receptors
ceptors. Endothelins have been implicated in the pain and
A number of other receptor systems have been reported hyperalgesia associated with inammation, skin incision, can-
to play a role in the peripheral modulation of nociceptor cer, and sickle cell crisis. ETB receptors have been reported
responsiveness. to mediate both pro- and antinociceptive effects. Activation
of ETB receptors on keratinocytes results in the release of
Vanilloid Receptors -endorphins, which inhibit nociceptor activity by binding to
The vanilloid receptor TRPV1 (also known as VR1) is present opioid receptors on the peripheral terminals of nociceptors
on a subpopulation of primary afferent bers and is activated (Khodorova et al 2003).
by capsaicin, heat, and protons (see Chapter 2). Following
inammation, axonal transport of TRPV1 mRNA is induced, Peripheral Modulators of Nociceptor
the proportion of TRPV1-labeled unmyelinated axons in
the periphery is increased by almost 100% (Carlton and
Coggeshall 2001), and the sensitivity of DRG neurons and GPCRs, present on the plasma membrane and terminals of
primary afferent bers to capsaicin increases (Nicholas et al nociceptive neurons, play an important role in the modula-
1999, Tohda et al 2001). Certain inammatory mediators, tion of pain signaling. GPCRs involved in antinociceptive
such as bradykinin, lower the threshold of TRPV1-mediated mechanisms include opioid, cannabinoid, SST, muscarinic
heat-induced currents in DRG neurons and increase the acetylcholine, -aminobutyric acid (GABAB), mGlu, and
proportion of DRG cells that respond to capsaicin (Stucky 2-adrenergic receptors (Fig. 1-13, for review see Pan et al
et al 1998, Sugiura et al 2002). NGF also potentiates the 2008). Most GPCR agonists that have antinociceptive action
responses of TRPV1, and NGF-induced thermal hyperalgesia are coupled to Gi/o proteins, which modulate voltage-gated
is absent in TRPV1 knockout mice. These observations, along Ca2+ channels and result in a decrease in presynaptic Ca2+
with other experiments performed in mice lacking TRPV1, entry and inhibition of neurotransmitter release. GPCRs also
indicate that this channel protein plays a critical role in modulate an inwardly rectifying K+ channel, the GIRK chan-
inammation-induced heat hyperalgesia (Caterina et al 2000, nel, which plays a critical role in maintaining resting mem-
Davis et al 2000). brane potential and excitability.
Inammatory mediators activate or sensitize TRPV1 The GPCRs on peripheral nociceptors are attractive poten-
through a diverse array of second-messenger pathways. For tial therapeutic targets for the development of new drugs that
example, the thermal hyperalgesia induced by bradykinin and may have some benet, in contrast to the more traditional
NGF is thought to be mediated, in part, by PLC-dependent analgesics, which work at the level of the CNS. Drugs acting
phosphorylation of TRPV1 by PKC. Activation of PLC also at the periphery and inhibiting the generation and signaling
leads to hydrolysis of the membrane phospholipid phosphati- of nociceptive input toward the spinal cord and the brain may
dylinositol 4,5-bisphosphate (PIP2) and consequent reversal prevent central plastic changes such as wind-up and central
of TRPV1 disinhibition by that lipid (Chuang et al 2001). sensitization. In addition, these drugs may provide analgesia
A PIP2 binding site that is critical for the thermal sensitivity of without the undesirable adverse effects, such as sedation, diz-
TRPV1 has been identied (Prescott and Julius 2003). Func- ziness, and cognitive dysfunction, associated with drugs act-
tional coupling between protein kinase A (PKA) and TRPV1 ing on the CNS system (see Stein et al 2009).

CRH cells

Anandamide, 2-AG



Glutamate SSTR

2 Nav


VGCC Initiation
Transduction Conduction

Ca2+ release

Figure 1-13. Potential peripheral modulatory mechanisms of nociceptor activity. Several metabotropic G proteincoupled receptors (GPCRs) may
play a role in inhibition of the initiation, transduction, or conduction of pain signals from peripheral nociceptive terminals. These GCPRs include opioid,
cannabinoid (CB), somatostatin (SSTR), muscarinic acetylcholine (M2), -aminobutyric acid B (GABAB), metabotropic glutamate (mGluR), adenosine 1 (A1),
and 2-adrenergic (2) receptors. Activation of these GCPRs by their endogenous ligands leads to inhibition of voltage-gated Ca2+ channels (VGCCs), which
results in a decrease in presynaptic Ca2+ entry and inhibition of neurotransmitter release. GPCRs also modulate an inwardly rectifying K+ channel, the GIRK
channel, which plays an important role in maintenance of the duration and excitability of the resting membrane potential. GPCRs also regulate the function
and kinetics of ion channels involved in sensory transduction, such as the transient receptor potential vanilloid (TRPV) channels and sodium channels (Nav).
(Artwork by Ian Suk, Johns Hopkins University.)

Opioids tissues. Inammatory cells such as macrophages, monocytes,

Besides their central analgesic action, morphine and other and lymphocytes contain opioid peptides. Release of endog-
opioids produce analgesia in inamed tissues by a peripheral enous opioids and antinociception can be induced by IL-1
mechanism (see Stein et al 2009). Opioid receptors have been and corticotropin-releasing hormone (CRH) originating from
demonstrated on the peripheral terminals of afferent bers, the inamed tissue.
and axonal transport of these receptors is enhanced during An alternative mechanism for activation of endogenous
inammation. Peripheral analgesia by opioids appears to be opioid analgesia at the site of tissue injury has been described
part of a physiological antinociceptive system since increased (see Khodorova et al 2009 for review). ET-1, a potent vaso-
amounts of endogenous opioids have been found in inamed active peptide, is synthesized and released by epithelia after
20 Section One | Neurobiology of Pain

tissue injury. Although ET-1 can trigger pain by activating arthritis. Synthetic SST agonists may have potential as anti-
ETA receptors on nociceptors, it also has an analgesic effect inammatory and analgesic drugs.
through its actions on ETB receptors. Activation of ETB
receptors on keratinocytes by ET-1 results in the release of Cholinergic Receptors
-endorphins and analgesia mediated via peripheral - and Non-neuronally released acetylcholine, acting on peripheral
-opioid receptors linked to GIRKs (see Fig. 1-13). cholinergic receptors, may have a modulatory role on noci-
ception. Nicotine has a weak excitatory effect on C-ber
Cannabinoids nociceptors and induces mild sensitization to heat, but no
Cannabinoids have recently emerged as a potential therapy alterations in mechanical responsiveness. In contrast, musca-
for chronic pain. Clinical use of non-selective cannabinoids rine desensitizes C nociceptors to mechanical and heat stimuli
is, however, limited by their CNS actions, which lead to (Bernardini et al 2001). Thus, nicotinic and muscarinic recep-
psychotropic effects, temporary memory impairment, and tors may have opposing effects on cutaneous nociceptors.
dependence. The endocannabinoid system includes the two Studies in mice with targeted deletions of the M2 receptor gene
cloned metabotropic receptors CB1 and CB2, possibly the suggest that M2 receptors on cutaneous nerve endings depress
orphan receptor GPR55, and the endogenous ligands anan- the responsiveness of nociceptive bers to noxious stimuli (see
damide and 2-arachidonoylglycerol. CB1 and CB2 receptors Wess et al 2003 for review). High levels of expression of M2
are GPCRs expressed in neural and non-neural immune cells. mRNA and considerably lower levels of M3 and M4 mRNA
They are distributed at many key sites in the pain-signaling are detected in medium-sized and small DRG neurons in the
pathway, including the peripheral and central terminals of rat (Tata et al 2000). M2, M3, and M4 muscarinic receptor
primary afferent bers, spinal dorsal horn neurons, and the subtypes may be involved in the modulation of nociceptive
brain stem and brain. CB1 and CB2 mRNA and protein are transduction.
widely expressed in the majority of DRG nociceptive neurons
(Agarwal et al 2007), and their expression has been shown to -Aminobutyric Acid Receptors
be up-regulated following inammation (Amaya et al 2006) The inhibitory neurotransmitter GABA activates both iono-
and nerve injury (Beltramo et al 2006, Mitrirattaanakul et al tropic (GABAA and GABAC) and metabotropic (GABAB)
2006). Multiple lines of evidence suggest that the analgesic receptors. GABAA receptors have been found in DRG cells
effects of CB1 and CB2 agonists may be mediated via their and on their central terminals in the dorsal horn. GABAA
actions on nociceptive primary afferents. Cannabinoids regu- receptors have been reported to be present in 1014% of the
late the function and kinetics of ion channels involved in sen- unmyelinated primary afferent axons in the glabrous skin
sory transduction, such as the TRP channels (e.g., TRPV1, of the cat (Carlton et al 1999). Behavioral studies suggest
TRPA1, TRPM8) and purinergic ion channels (P2X2, P2X2/3), a bimodal effect of GABAA receptors on the modulation of
as well as channels that directly affect neuronal excitability peripheral nociceptive transmission; a low concentration
(various K+ and Ca2+ channels). Studies in animal models sug- of GABAA agonists attenuates and a high concentration
gest that peripheral CB1 and CB2 receptors may be important enhances formalin-induced pain behavior. GABAB receptors
targets in controlling the pain associated with inammation, are also present in primary afferents, and GABAB mRNA is
neuropathy, and bone cancer (see Anand et al 2009, Kress and expressed in DRG cells (Towers et al 2000). Degeneration
Kuner 2009 for reviews). CB receptor agonists also enhance of primary afferent bers by administration of capsaicin to
the analgesic effects of opioid agonists and non-steroidal anti- neonatal rats decreases GABAB receptor density by 50%,
inammatory drugs in experimental pain models. thus indicating that these receptors are localized in TRPV1-
expressing nociceptive afferents (Price et al 1987). Activa-
Somatostatin tion of the GABAB receptor by agonists such as baclofen
SST is a regulatory peptide that is widely distributed in neural inhibits neuronal excitability by inhibition of N-type Ca2+
and non-neural cells such as immune cells, broblasts, and currents and potentiation of voltage-dependent K+ currents
neuroendocrine cells. Found in a subpopulation of capsaicin- (Takeda et al 2004).
sensitive peptidergic DRG neurons, SST binds to G protein
coupled membrane receptors. Activation of SST receptors 2-Adrenoceptors
opens various K+ channels and inhibits voltage-gated Ca2+ Traditionally, the analgesic effects of 2-adrenergic agonists,
channels, which results in its anti-inammatory and analge- such as clonidine and dexmedetomidine, are thought to be sec-
sic effects. SST decreases the release of peptides such as SP ondary to their actions in the CNS (for review see Pertovaara
and CGRP from sensory nerve endings in the periphery and 2006). However, peripheral 2-adrenoceptors may also be
reduces neurogenic inammation (for review see Pinter et al involved in modulation of nociceptor activity. Studies using
2006). The analgesic effects of SST are thought to result from selective 2-subtype knockout mice have shown that the 2A-
inhibition of the TRPV1 ion channel (Carlton et al 2004) and adrenergic receptors are primarily involved in the analgesic
possibly via an interaction with opioid receptors. Intraplantar effect of 2-adrenoceptor agonists (Stone et al 1997). Selec-
administration of the SST receptor agonist octreotide reduces tive removal of TRPV1-expressing sensory neurons induces
the phase II response after formalin injection, decreases the a large decrease in 2A- but not in 2C-adrenoceptors in the
response of CMHs to heat stimuli, and attenuates the ther- spinal dorsal horn, which suggests that 2A-adrenoceptors
mal responses of nociceptors sensitized by bradykinin. Endog- are located on the central terminals of primary afferent neu-
enous release of SST from nociceptive afferents is considered rons whereas the 2C subtype is located primarily on spinal
to play a modulatory role in inammatory and neuropathic dorsal horn neurons (Stone et al 1998, Chen et al 2007). 2-
pain. Intra-articular injection of SST into the knee resulted Adrenergic agonists may inhibit the depolarization-induced
in pain relief in patients with osteoarthritis and rheumatoid Ca2+ inux and induce a GIRK current in nociceptors.

SECOND MESSENGERS AND SIGNAL hyperalgesia to heat lasts longer67 days after plantar inci-
TRANSDUCTION PATHWAYS sion. As with other types of tissue injury, secondary hyperal-
gesia after incision injury is present only to mechanical, not
As described above, inammation is associated with the release thermal, stimuli (Pogatzki et al 2000). The incision-induced
of a host of chemical mediators (Fig. 1-12). Although some primary and secondary hyperalgesia results from character-
of these agents may directly activate nociceptors, most of the istic peripheral, spinal, and supraspinal mechanisms (Zahn
inammatory mediators lead to changes in the sensory neuron and Brennan 1999, Pogatzki et al 2002). The conversion of
rather than directly activating it. Such changes in sensory neu- mechanically insensitive silent nociceptors to mechanically
rons include early post-translational alterations in the periph- responsive bers may play an important role in the mainte-
eral terminals of nociceptors (peripheral sensitization) and a nance of primary mechanical hyperalgesia (Pogatzki et al
delayed transcription-dependent alteration (see Woolf and 2002). Release of ATP from injured cells is considered to play
Costigan 1999, Kidd and Urban 2001). Peripheral sensitization an important role in the induction of mechanical allodynia
can be the result of changes in the transducer molecule (e.g., after a skin incision (Tsuda et al 2001).
TRPV1 receptor) or in voltage-gated ion channels (e.g., sodium The incision-induced spontaneous activity in primary afferent
channels) secondary to the phosphorylation of membrane- bers plays a critical role in maintaining widedynamic range
bound proteins. Inammation can also induce delayed and neurons in the dorsal horn in a sensitized state. In contrast to
longer-lasting transcription-dependent changes in effector genes the central mechanisms of hyperalgesia following other forms
in DRG cells as a result of electrical activity and retrograde of cutaneous injury where N-methyl-d-aspartate (NMDA)
transport of specic signal molecules such as NGF. An increase receptors play a critical role, the hyperalgesia that results from
in intracellular calcium induced by electrical activity activates an incision is characterized by distinct pharmacological mecha-
a host of intracellular transcription factors such as the cAMP- nisms that are not dependent on NMDA receptors.
response elementbinding protein (CREB; Ji and Rupp 1997).
Considerable attention has been focused on the signal trans- ROLE OF THE SYMPATHETIC NERVOUS
duction mechanisms of primary afferent neurons and their
alteration by inammation. Two principal signaling pathways
have been postulated to mediate inammation-induced hyper- Nociceptors normally do not respond to sympathetic stimu-
algesia. Inammatory mediators such as PGE2, serotonin, and lation. In addition, sympathectomy plus depletion of cat-
adenosine activate PKA (Gold et al 1998), whereas NGF, brady- echolamine stores with reserpine has no effect on acute
kinin, and epinephrine induce hyperalgesia in part by activating inammation. In contrast, sympathectomy reduces the sever-
PKA but also through an isozyme of PKC (Khasar et al 1999). ity of injury in chronic adjuvant-induced arthritis (see Raja
PKA and PKC sensitize nociceptors to heat by modulating the 1995, Jnig et al 1996 for reviews). Inammation may lead
activity of TTX-resistant sodium currents. As described above, to catechol sensitization of cutaneous nociceptors. Sympa-
these signaling pathways also interact with the heat transducer thetic stimulation and close arterial injection of norepineph-
TRPV1, which results in sensitization of the receptor to heat. rine (NE) also excite 3540% of C-polymodal nociceptors in
MAPKs are also reported to be involved in the transduction chronically inamed rats (Sato et al 1993). This adrenergic
of extracellular stimuli (e.g., signals from extracellular growth activation of nociceptors was blocked by 2- but not by 1-
factors such as NGF) into diverse intracellular responses and adrenergic antagonists. Sympathetic efferent bers are also
neuronal plasticity. Three subfamilies of MAPKs have been thought to play a role in neurogenic inammation.
well characterizedthe extracellular signalregulated kinases In human skin sensitized by the topical application of cap-
(ERKs), the c-Jun amino-terminal kinases (JNKs), and the p38 saicin, hyperalgesia persists longer at sites where exogenous
enzymes. ERK is present in primary afferent neurons, is phos- NE was administered, and this -adrenoceptormediated
phorylated by nociceptive stimuli, and is thought to play a role effect was independent of the vasoconstrictor response
in inammatory hyperalgesia (Dai et al 2002). Inammation (Drummond 1995, 1996). Additionally, local administra-
also activates p38 in the soma of C-ber nociceptive cells in tion of an -adrenergic antagonist reduced the spontaneous
the DRG (Ji et al 2002). Inhibiting the activation of p38 in the pain and hyperalgesia resulting from the intradermal injec-
DRG reduces the inammation-induced increase in TRPV1 tion of capsaicin (Kinnman et al 1997). However, physiologi-
receptors in the DRG and attenuates heat hyperalgesia. Acti- cal modulation of sympathetic vasoconstrictor activity by
vation of p38 in the DRG is dependent on peripheral produc- whole-body warming or cooling does not alter the intensity
tion of NGF during inammation. Thus, MAPKs and NGF or spatial distribution of capsaicin-evoked spontaneous pain
play important regulatory roles in TRPV1 receptor expression and mechanical hyperalgesia (Baron et al 1999). Anatomi-
and maintenance of heat hyperalgesia after inammation. cal studies indicate that SP and NMDA receptor mRNA is
up-regulated in preganglionic sympathetic neurons after paw
POSTOPERATIVE PAIN inammation in rats (Ohtori et al 2002). These changes are
AND HYPERALGESIA postulated to possibly be evidence of a role of the sympathetic
nervous system in inammatory hyperalgesia.
The pain resulting from different tissue injuries may differ in
its characteristics and mechanisms. Postoperative, incisional
pain is a unique but common form of acute pain. Studies
in rodents have characterized the primary hyperalgesia to An understanding of secondary hyperalgesia is important not
mechanical and thermal stimuli caused by a surgical inci- only with regard to understanding the neural mechanisms
sion (Brennan et al 1996, Pogatzki and Raja 2003). Primary of acute pain but also with regard to understanding many
hyperalgesia to mechanical stimuli lasts for 23 days, whereas aspects of chronic pain. In this section we consider the nature
22 Section One | Neurobiology of Pain

of secondary hyperalgesia and its possible peripheral and cen-

A C Site A
tral mechanisms.
Secondary Hyperalgesia to Mechanical 5.0
but Not Heat Stimuli
Primary hyperalgesia is characterized by the presence of after
enhanced pain in response to heat and mechanical stim- 3.0
uli, whereas secondary hyperalgesia is characterized by Mechanical 2.0 before
enhanced pain in response to only mechanical stimuli (e.g., hyperalgesia
Ali et al 1996). In one study in which the sensory changes A 1.0
that occur in the zones of primary and secondary hyperal- B
Flare 0
gesia were compared (Raja et al 1984), burn injuries were
D Site B
induced in two locations on the glabrous skin of the hand

Normalized pain ratings

in human subjects (Fig. 1-14). Within minutes of the injury, 1 cm 2.0
lightly touching the skin at the site of the two burns, as well
1.5 before
as in a large area surrounding the burns, caused pain. The
decrease in the pain threshold to von Frey hairs in the pri- 1.0 after
mary (injured) zone was similar to that in the area of second- B
ary hyperalgesia (Fig. 1-14B). Marked hyperalgesia to heat 0.5

Mechanical pain thresholds (bars)

was observed in the area of primary hyperalgesia (site A, 0
16 Before burn
the injury site, Fig. 1-14C). In the uninjured region between After burn
14 E Site C
the two burns, however, the painfulness of the heat stimuli
actually decreased (Fig. 1-14D). Notably, the area between 12 2.0
the burns was hypo-algesic to heat while being hyperalgesic 10
to mechanical stimuli. 8 after
6 1.0
Spreading Sensitization of Nociceptors 4
Does Not Occur 2
0 0
Activation of nociceptors leads to a are response (discussed Site Site Site 41 43 45 47 49
in more detail below). This response is neurogenic in the A B C
Stimulus temperature (C)
sense that it depends on intact innervation of the skin by
nociceptors. The are response extends well outside the area Figure 1-14. Hyperalgesia to mechanical and heat stimuli develops at
of initial injury. One explanation for the are response is the site of injury (zone of primary hyperalgesia), whereas hyperalgesia
that it involves spreading activation of nociceptors. Acti- to mechanical but not heat stimuli develops in the uninjured area sur-
rounding an injury (zone of secondary hyperalgesia). A, Two burns (53C,
vation of one nociceptor leads to the release of chemicals 30 seconds) were applied to the glabrous skin of the hand (sites A and D).
that activate neighboring nociceptors, which leads to further Mechanical thresholds for pain and ratings of pain in response to heat stimuli
release of chemicals and activation of additional nocicep- were recorded before and after the burns at one of the injury sites (site A), in
tors. Lewis (1942) believed that a similar mechanism, which the uninjured skin between the two burns (site B), and at an adjacent site (site
he termed spreading sensitization, accounted for secondary C). The areas of are and mechanical hyperalgesia following the burns in one
subject are also shown. In all subjects, the area of mechanical hyperalgesia was
hyperalgesia. Activation and sensitization of one nocicep- larger than the area of are. Mechanical hyperalgesia was present even after
tor lead to spread of this sensitization to another nocicep- the are disappeared. B, Mean mechanical thresholds for pain before and after
tor, possibly because of the effects of a sensitizing substance burns. The mechanical threshold for pain was signicantly decreased follow-
released from the nociceptor initially activated. Another ing the burn. The mechanical hyperalgesia was of similar magnitude at each of
the three test spots (A, B, C). CE, Mean normalized ratings of the painfulness
theoretical possibility is that coupling between nociceptors of heat stimuli (same as described in Fig. 1-5) before and after burns. C, At
increases after injury. burn site A, all the characteristics of heat hyperalgesia (i.e., decrease in pain
Several lines of evidence indicate that spreading sensitiza- threshold, increased pain in response to suprathreshold stimuli, and spontane-
tion does not occur: ous pain) were observed after the burns. D, In the uninjured area between the
A heat injury to half the receptive eld of nociceptors does two burns (site B), pain ratings decreased after the burns. Thus, heat hypalge-
sia was observed. E, At site C, pain ratings before and after the burns were not
not alter the sensitivity of the other half to heat stimuli signicantly different. (Note that a different scale is used in C.) (Reproduced
(Thalhammer and LaMotte 1983). with permission from Raja SN, Campbell JN, Meyer RA 1984 Evidence for
A mechanical injury adjacent to the receptive eld of noci- different mechanisms of primary and secondary hyperalgesia following heat
ceptors fails to alter the responses of CMHs in the monkey injury to the glabrous skin. Brain 107:11791188.)
(Campbell et al 1988a) and rat (Reeh et al 1986).
Antidromic stimulation of nociceptive bers in the monkey Other differences exist between are and secondary hyperal-
(Meyer et al 1988) and rat (Reeh et al 1986) does not cause gesia (LaMotte et al 1991):
sensitization. The zone of secondary hyperalgesia is generally larger than
Application of mustard oil to one part of the receptive eld the zone of are.
of C-ber nociceptors in humans does not lead to sensiti- Flare can be induced without causing secondary hyperalge-
zation of other parts of the receptive eld (Schmelz et al sia (for example, with histamine), and secondary hyperal-
1996). gesia can be induced without a are response.

Secondary hyperalgesia does not spread beyond the bodys

midline, whereas the are response does. A

Central Mechanisms of Secondary

If peripheral sensitization does not account for secondary
hyperalgesia, the mechanisms noted in Figure 1-10CF should Nerve block
be examined in the CNS. Indeed, it has been relatively easy
to demonstrate enhanced responsiveness of CNS neurons to
mechanical stimuli after cutaneous injury (e.g., Simone et al
1991b). Substantial evidence favors the following important
tenet: the peripheral signal for pain does not reside exclu-
sively with nociceptors. Under pathological circumstances,
other receptor types, which are normally associated with the
sensation of touch, acquire the capacity to evoke pain. This
principle applies not only to secondary hyperalgesia but also
to neuropathic pain states in general. This condition arises in
part through augmentation of the responsiveness of central
pain-signaling neurons to input from low-threshold mechano-
receptors, a phenomenon often termed central sensitization.
35 min 180 min
Many of the insights acquired about secondary hyperalge-
sia have been gained from studies with capsaicin. Investiga- B
tors have been drawn to the use of capsaicin as the injury
stimulus for several reasons:
Capsaicin selectively activates nociceptors (Szolcsnyi
Capsaicin causes intense pain and a large zone of secondary
hyperalgesia when applied topically or intradermally to the
skin (Simone et al 1989).
Injection of capsaicin into the skin does not produce any
apparent tissue injury.
The characteristics of hyperalgesia resemble those for heat Control
or cut injuries. Immediately around the injection site, heat
and mechanical hyperalgesia is present. Outside this area of
primary hyperalgesia is a large zone of secondary hyperal-
gesia characterized by mechanical hyperalgesia but not heat
hyperalgesia (Ali et al 1996).
LaMotte and colleagues performed a number of pivotal exper-
iments to determine the relative importance of peripheral and
central sensitization in secondary hyperalgesia (LaMotte et al
1991). To test whether peripheral nerve bers are sensitized,
capsaicin was administered under conditions of a proximal 35 min 180 min
nerve block, and the magnitude of hyperalgesia was deter-
mined after the effects of the anesthetic dissipated. When the 2 cm
relevant nerve is blocked proximal to the capsaicin injection
Figure 1-15. A proximal nerve block prevents the development of sec-
site, the CNS is spared the nociceptive input generated at the ondary hyperalgesia. A, After blockade of the lateral antebrachial nerve
time of injection. The effects of capsaicin on the peripheral with 1% Xylocaine, capsaicin (100 g in 10 L) was injected into the anes-
nervous system are not affected (e.g., a are develops) since thetic skin. A are (dashed line) developed within 5 minutes. No hyperalgesia
the nerve block is proximal to the area of capsaicin applica- was present 180 minutes after the capsaicin injection when the local anes-
thetic block had dissipated. B, On the control arm, normal are and hyper-
tion. Figure 1-15 shows the results of this experiment in one algesia in response to stroking (dotted line) and punctate (solid line) stimuli
subject. No hyperalgesia was present after the block had worn developed within 5 minutes. Hyperalgesia to punctate stimuli was still pres-
off. Thus, when the CNS is spared the input of nociceptors ent 180 minutes after the capsaicin injection. (Adapted from LaMotte RH,
at the time of the acute insult, hyperalgesia does not develop Shain CN, Simone DA, et al 1991 Neurogenic hyperalgesia: psychophysical
(LaMotte et al 1991, Pedersen et al 1996). studies of underlying mechanisms. Journal of Neurophysiology 66:190211.)
Additional evidence that central sensitization, not periph-
eral sensitization, plays a major role in secondary hyperalge-
sia includes the following: When an anesthetic strip is produced in the skin, electrical
Electrical stimulation of the skin can be used to produce a stimulation on one side of the anesthetic strip produces a
large zone of secondary hyperalgesia (Koppert et al 2001). are only on that side of the strip, thus indicating that the
Electrical stimulation directly activates the axon and there- strip has blocked the axon reexive are; secondary hyper-
fore bypasses a peripheral receptor mechanism. algesia develops symmetrically around the stimulation site
24 Section One | Neurobiology of Pain

and extends well beyond the anesthetic strip (Klede et al Stroking hyperalgesia after capsaicin injection lasts 12
2003). hours, whereas punctate hyperalgesia lasts more than
Secondary hyperalgesia following injection of capsaicin 12 hours (LaMotte et al 1991).
within the territory of a given nerve spreads into the terri- Punctate hyperalgesia, not stroking hyperalgesia, devel-
tory of an adjacent nerve (Sang et al 1996). oped after intradermal capsaicin injection into the arm of
a patient with a severe large-ber neuropathy (Treede and
Different Mechanisms for Stroking Cole 1993). This evidence suggests that punctate hyperalge-
sia is mediated by small-diameter (presumably nociceptive)
and Punctate Hyperalgesia
Two distinct forms of mechanical hyperalgesia are observed The pain produced by touching the skin with different
in the zone of secondary hyperalgesia: punctate hyperalgesia wool fabrics was greatly increased in the region of second-
and stroking hyperalgesia. Hyperalgesia to blunt pressure is ary hyperalgesia (Cervero et al 1994). The pain was pro-
not observed in the secondary zone (Koltzenburg et al 1992). portional to the prickliness of the fabrics. Since nociceptors
We will rst consider stroking hyperalgesia (also called allo- and not low-threshold mechanoreceptors exhibit a differ-
dynia). Stroking hyperalgesia appears to be mediated by activ- ential response to different wool fabrics (Garnsworthy et al
ity in low-threshold mechanoreceptors. When a pressure cuff 1988), activity in nociceptors probably contributes to this
was used to selectively block myelinated bers, the pain in form of secondary hyperalgesia to wool fabrics.
response to stroking disappeared at a time when touch sensa- When the area of primary hyperalgesia is anesthetized or
tion was lost but heat and cold sensations were still present cooled, stroking hyperalgesia is eliminated but punctate
(LaMotte et al 1991, Koltzenburg et al 1992). This is also hyperalgesia persists (LaMotte et al 1991). Therefore,
true in patients with stroking hyperalgesia from neuropathic stroking hyperalgesia has an ongoing dependence on input
pain (Campbell et al 1988b). In another series of experi- from the sensitized area, whereas punctate hyperalgesia is
ments, Torebjrk and colleagues (1992) performed intraneu- more enduring and less dependent on ongoing discharge
ral microstimulation in awake human subjects. As shown in from the sensitized area.
Figure 1-16, stimulation of primary afferent bers normally The pain in response to a controlled punctate stimulus does
concerned with tactile sensibility evoked pain when (but not not vary signicantly across the zone of secondary hyperal-
before) secondary hyperalgesia was produced. gesia but decreases precipitously at the border (Huang et al
Punctate hyperalgesia is manifested by heightened pain 2000). This suggests that the sensitization responsible for
associated with the application of small, stiff, or sharp probes secondary hyperalgesia is an all-or-nothing phenomenon. In
to the skin (e.g., von Frey monolaments). Several lines of addition, subjects were able to grade the magnitude of pain
evidence indicate that punctate hyperalgesia has a different from stimuli of different intensity. Interestingly, although the
neural mechanism than stroking hyperalgesia does and is threshold for pain in response to punctate stimuli decreases in
mediated by central sensitization to activity in nociceptors: the zone of secondary hyperalgesia (Magerl et al 1998), the
The area of punctate hyperalgesia is consistently larger than threshold for touch detection increases (Magerl and Treede
that of stroking hyperalgesia. 2004).


Stimulation Stimulation Stimulation

Tactile Tactile sensation Tactile

sensation and pain sensation


Figure 1-16. Microneurographic evidence that large-diameter myelinated bers are involved in the pain observed in the zone of secondary
hyperalgesia. A, Intraneural electrical stimulation of the supercial peroneal nerve at a xed intensity and frequency evoked a purely tactile (non-painful)
sensation projected to a small area of skin on the dorsum of the foot (dark blue area). B, After intradermal injection of capsaicin (100 g in 10 L) adjacent
to the projected zone (at the site indicated by the open circle), a zone of secondary hyperalgesia (indicated by light blue area) developed that overlapped the
sensory projection eld. Now, intraneural stimulation at the same intensity and frequency as in A was perceived as a tactile sensation accompanied by pain. C,
When the zone of secondary hyperalgesia no longer overlapped the sensory projection eld, the intraneural stimulation was again perceived as purely tactile,
without any pain component. (Adapted from Torebjrk HE, Lundberg LER, LaMotte RH 1992 Central changes in processing of mechanoreceptive input in
capsaicin-induced secondary hyperalgesia in humans. Journal of Physiology [London] 448:765780.)

Model for Stroking Hyperalgesia Model for Punctate Hyperalgesia

From the above we know that secondary hyperalgesia to Punctate hyperalgesia appears to be mediated by central sen-
stroking stimuli appears to be due to sensitization of cen- sitization to nociceptor input. However, most nociceptors
tral pain-signaling neurons to the input from low-threshold respond to heat stimuli. Why is there not hyperalgesia to heat
mechanoreceptors (Fig. 1-17). In normal skin, activity in stimuli in the secondary hyperalgesic zone? One possibility
low-threshold mechanoreceptors signals touch sensation is that this central sensitization involves a mechano-specic
(Fig. 1-17A). As a result of the barrage of activity in noci- channel. In this model, punctate hyperalgesia is mediated by
ceptors, sensitization occurs in the CNS such that input mechano-specic nociceptive afferents that project via sensi-
from low-threshold mechanoreceptors gains access to the tized mechano-specic interneurons to central pain-signaling
pain system (Fig. 1-17B). Now, light touching of the skin is neurons. Support for this hypothesis comes from experi-
painful. Plasticity in the response of second-order neurons in ments in which the skin was pretreated with topical capsaicin
the dorsal horn appears to be a major factor that accounts to eliminate epidermal nerve bers that are sensitive to heat
for this central sensitization (see Chapter 6 for detailed dis- (Nolano et al 1999). Such treatment led to a lack of pain in
cussion). However, another possibility that involves plas- response to heat stimuli; however, secondary hyperalgesia
ticity in primary afferents is that mechanoreceptors gain to punctate stimuli developed after the injection of capsaicin
access to nociceptive neurons by means of a presynaptic link into nearby untreated skin (Fig. 1-18; Fuchs et al 2000). Addi-
(Cervero et al 2003; see discussion below on primary affer- tional experiments with selective nerve ber blocks revealed
ent depolarization). that the punctate hyperalgesia disappeared when A bers
were blocked (Magerl et al 2001). Thus, punctate hyperalge-
sia appears to be signaled by A-ber afferents that are insen-
A Peripheral nervous system Central nervous system sitive to capsaicin and heat.
One well-studied form of central sensitization, termed wind-
Noxious stimulus horn up, is characterized by a slowly increasing response of central
neurons to repeated C-ber stimulation at rates greater than
0.3 Hz (e.g., Mendell and Wall 1965). The perceptual cor-
Nociceptors CPSNs
relate of wind-up is temporal summation (Price et al 1977).
Low-threshold A Capsaicin Capsaicin Vehicle
mechanoreceptors Dorsal pretreatment area injection site pretreatment area

Touch, pressure


Zone of
B secondary
hyperalgesia 1 cm
Central Pain
Inflammation sensitization
0.8 0.8
Normalized pain ratings

Normalized pain ratings

Spontaneous activity CPSNs

Dorsal 0.6 0.6
in nociceptors
Low-threshold 0.4 0.4
mechanoreceptors Dorsal
nuclei 0.2 0.2
Touch, pressure
Primary hyperalgesia
Secondary hyperalgesia 0.0 0.0
Pre Post Pre Post

Figure 1-17. Central sensitization accounts for secondary hyperalgesia. Figure 1-18. Secondary hyperalgesia to punctate mechanical stimuli
A, Nociceptors signal acute pain. Noxious stimuli selectively activate noci- occurs in skin that has been pretreated with topical capsaicin, which
ceptors that project to central pain-signaling neurons (CPSNs) in the spinal desensitizes unmyelinated, epidermal nerve bers. A, Capsaicin was
cord. The CPSNs project to higher centers, where pain is perceived. Low- applied to a 2 2-cm area on the volar aspect of the forearm to produce
threshold mechanoreceptors convey the sensation of touch. B, Injury or desensitization of the skin to heat stimuli. A nearby vehicle-treated area served
inammation leads to the sensitization of primary afferent nociceptors. The as control. Two days later, capsaicin was injected intradermally between the
enhanced responsiveness or sensitization of primary afferents accounts for two treatment areas and produced a large, symmetrical zone of secondary
primary hyperalgesia. Spontaneous activity also develops in the nociceptors hyperalgesia to punctate mechanical stimuli. B, Pain ratings in response to
and drives the development of sensitization of the CPSNs. This central sen- a sharp probe increased dramatically 60 minutes after the capsaicin injec-
sitization involves enhanced connectivity between low-threshold mechanore- tion. The average pain ratings at the capsaicin pretreatment area (left panel)
ceptors and CPSNs. Now, signals from low-threshold mechanoreceptors gain were not signicantly different from those at the vehicle treatment area (right
access to the pain pathway, which leads to the development of secondary panel). (Adapted from Fuchs PN, Campbell JN, Meyer RA 2000 Secondary
hyperalgesia to mechanical stimuli. hyperalgesia persists in capsaicin desensitized skin. Pain 84:141149.)
26 Section One | Neurobiology of Pain

The nding that temporal summation does not change in the that are mimicked by vasoactive neuropeptides are contrac-
zone of secondary hyperalgesia argues against wind-up as a tion of smooth muscles, stimulation of mucous secretion from
mechanism for secondary hyperalgesia (Magerl et al 1998). airways, and leukocyte adhesion. Some efferent functions of
nociceptors and the chemical mediators involved are shown
Flare is thought to be due to a peripheral axon reex. Acti-
vation of one branch of a nociceptor by a noxious stimulus
Aging induces changes in the properties of unmyelinated results in the antidromic invasion of action potentials into
nociceptive afferents (Namer et al 2009). Thus, the per- adjacent branches of the nociceptor, which in turn causes
centage of mechanosensitive afferents decreased whereas the release of vasoactive substances from terminals of the
the percentage of mechano-insensitive afferents increased, nociceptor. Capsaicin-sensitive A- and C-ber nociceptors
and some bers showed signs of sensitization, desensitiza- are thought to be involved in the are reaction. However,
tion, and spontaneous activity, features previously observed the extent of the are far exceeds the size of the receptive
in patients with neuropathic pain. In addition, changes in elds of conventional nociceptors. A possible explanation
the conductive properties of nociceptive afferents were also for this discrepancy is that the are is mediated, at least
observed. The mechanisms underlying these changes are in part, by a subpopulation of chemosensitive nociceptive
unknown, but they may, for example, be due to a dimin- bers with large receptive elds. Some C-bers with large,
ished supply of neurotrophic factors. It has been hypoth- complex receptive elds have been reported (Meyer et al
esized that age-related changes could render nociceptive 1991, Schmelz et al 1997). Transcutaneous electrical stimu-
afferents more susceptible to neuropathy-inducing insults lation studies in the skin of human volunteers suggest that
(Namer et al 2009). the axon reex are, measured by laser Doppler imaging,
was mediated via mechano-insensitive C-ber nociceptors
Several lines of evidence indicate that the neural substrates
for vasodilatation and the perception of pain are different.
Nociceptors, apart from signaling pain, serve regulatory (1) The magnitude of the vasodilatation induced by a nox-
and trophic functions. An efferent role for nociceptors was ious stimulus does not always increase with the intensity of
suggested by several investigators almost a century ago (see pain (Koltzenburg and Handwerker 1994). (2) Low activity
Lynn 1996 for historical review). Two efferent cutaneous (<1 Hz) in C bers can generate signicant vasodilatation
phenomena have been considered to be dependent on the (Lynn and Shakhanbeh 1988), but in humans does not cause
integrity of afferent nociceptive bers and are part of the any conscious sensation. (3) Histamine can produce a large
so-called neurogenic inammation: vasodilatation, which are with little or no pain. Possible explanations are that dif-
becomes visible as a are surrounding a site of injury, and ferent discharge patterns are needed for pain versus are in a
plasma extravasation, which is manifested as a wheal at the given ber population or certain classes of afferents are better
site of injury. Several peptides have been identied in the designed for are than for pain and vice versa.
peripheral terminals of sensory neurons, including SP and Similarly, pain sensations and plasma extravasation have
other tachykinins such as neurokinins A and K, CGRP, independent mechanisms. The ability of inammatory media-
SST, and vasoactive intestinal polypeptide. The presence tors such as bradykinin, histamine, and serotonin to induce
and release of SP and CGRP from capsaicin-sensitive sen- plasma extravasation and excite nociceptors, as assessed by
sory nerve endings in experimental animals, their ability pain ratings and are response, has been examined in humans.
to induce many of the signs of acute inammation, includ- In healthy human skin, no clear relationship between nocicep-
ing vasodilatation and plasma extravasation, and inhibi- tor activation and plasma extravasation could be established.
tion of neurogenic vasodilatation by selective neuropeptide For example, bradykinin induced protein extravasation with-
antagonists suggest that they may be the principal mediators out pain or are, and serotonin evoked pain and are at con-
of neurogenic inammation and axon reexive are. SP- centrations that did not induce plasma extravasation. These
induced vasodilatation and plasma extravasation may result observations suggest that the plasma extravasation induced
from a direct effect on the vasculature or be due to release of by these mediators is mostly non-neurogenic in mechanism
histamine by degranulation of mast cells by SP. Differences (Lischetzki et al 2001).
in neurogenic inammation and peptide release in rat and Antidromic activity involved in the effector responses can
human skin have, however, been observed. Electrical stimu- also originate from the spinal cord. A series of studies in a
lation results in release of CGRP and SP in rat and human model of acute arthritis indicated that primary afferent input
skin. However, unlike rat skin, the endogenous release of to the spinal cord activates multisynaptic central neuronal
peptides after strong chemical or electrical stimulation is pathways, which in turn inuence the development of neuro-
not associated with neurogenic protein extravasation or genic inammation (for review see Sluka et al 1995). Activa-
release of mast cell mediators in human skin (see Schmelz tion of primary afferent bers may result in depolarization of
and Petersen 2001 for review). the central terminals of other afferent bers (primary afferent
SP and CGRP are also reported to play a role in immu- depolarization [PAD]). If PAD is large enough (e.g., under
nological processes (e.g., migration of leukocytes to sites of peripheral inammatory conditions), the depolarization can
tissue injury), and they stimulate epidermal cells (e.g., kerati- be sufcient to initiate action potentials at the central termi-
nocytes and Langerhans cells) necessary for the maintenance nals that are conducted antidromically in the primary afferent
and repair of skin integrity (for reviews see Maggi and Meli bers (dorsal root reexes [DRRs]). It is postulated that the
1988, Holzer 1998). Other efferent actions of nociceptors antidromic impulses (DRRs) triggered by PAD result in the

Mast cell

stimulation Keratinocyte
proliferation 3
Arteriole dilation


Immune cell
Post capillary

Plasma 4


Smooth muscle

Figure 1-19. Efferent actions of nociceptors. A noxious stimulus leads to action potentials in nociceptive bers that propagate not only to the central
nervous system but also antidromically into peripheral branches. These antidromic action potentials lead to the release of neuropeptides such as substance P,
calcitonin generelated peptide (CGRP), and neurokinin A (NKA). These substances can stimulate epidermal cells (1) and immune cells (2) or lead to vasodi-
latation (3), plasma extravasation (4), and smooth muscle contraction (5). (Artwork by Ian Suk, Johns Hopkins University.)

release of neuropeptides in the joint from peripheral terminals NOCICEPTORS AND NEUROPATHIC PAIN
of the afferents and contribute to the inammatory process.
DRRs have been recorded in C, A, and A ber types in A well-known axiom in the eld of pain is that injury to the
rat models of acute arthritis. The joint inammation and the nociceptive pathways, whether it be in the peripheral ner-
DRRs were attenuated by prior dorsal rhizotomy. vous system or CNS, carries with it the liability that pain may
Cervero and Laird proposed that the DRRs may also result. This is paradoxical in the sense that lesions should,
explain secondary hyperalgesia (Cervero et al 2003). Accord- one would think, lead to decits in function. The ongoing
ing to this hypothesis, the action potentials initiated in pri- pain in patients is frequently associated with enhanced pain
mary afferent bers as a result of enhanced PAD propagate in response to natural stimuli, a phenomenon termed hyperal-
peripherally to produce are and centrally to evoke pain sen- gesia. Hyperalgesia may be prominent in neuropathic condi-
sation. As evidence to support this hypothesis, they reported tions such as post-herpetic neuralgia, certain cases of diabetic
that light stroking of the skin leads to an increase in blood or human immunodeciency virusassociated neuropathy,
ow in the zone of secondary hyperalgesia, but not in normal and certain cases of traumatic nerve injury. In this section we
skin. consider the role of altered function of nociceptors in neuro-
Nociceptive innervation of the skin has been suggested to pathic pain.
also play a critical role in wound healing. Sensory denerva- In considering inammatory pain it was noted earlier in this
tion by capsaicin injection impairs cutaneous wound healing chapter that primary hyperalgesia is explained by sensitiza-
in rats (Smith and Liu 2002). Skin denervation decreases kera- tion of nociceptors whereas secondary hyperalgesia is due to
tinocyte proliferation and leads to decreased skin thickness central sensitization. In the case of secondary hyperalgesia,
(Hsieh and Lin 1999). The role of cutaneous nociceptors in the input of low-threshold mechanoreceptors, normally con-
wound healing may be due to neuromodulatory actions of the cerned only with touch sensibility, leads to pain because the
sensory peptides SP and CGRP, which when injected at skin synaptic links with central pain-signaling cells in the dorsal
wound sites, promote wound healing in aged rats (Khalil and horn are strengthened. A similar mechanism of central sen-
Helme 1996). sitization appears to also explain the allodynia seen with
28 Section One | Neurobiology of Pain

neuropathic pain states. This was demonstrated in human this is done pre-emptively (before the L5 spinal nerve is sev-
subjects by selectively blocking the neural activity in large ered) or after the lesion. Thus, interruption of input from the
bers (touch bers) with an ischemic block. When touch sen- injured L5 spinal nerve fails to reverse the hyperalgesia in the
sation was eliminated and the functions of other nerve bers foot, which indicates that ectopic activity from the injured
were still preserved, the allodynia disappeared (Campbell et al nerve is not essential for the development of neuropathic pain
1988b). (Li et al 2000). (2) Electrophysiological recordings from the
The relative role of central and peripheral mechanisms in uninjured L4 spinal nerve (the root that most overlaps the
neuropathic pain is not well understood and probably varies innervation territory of the L5 root) reveal abnormal spon-
not only with the disease but also with factors such as genetic taneous activity in C-ber nociceptors. The spontaneous
differences. In many cases, however, the abnormal input of activity appears to emanate at least in part from the skin (Wu
neural activity from nociceptive afferents plays a dynamic and et al 2001). (3) Molecules related to pain (e.g., CGRP, brain-
ongoing role in maintenance of the pain state. derived neurotrophic factor [BDNF], VR1) are up-regulated
Understanding of neuropathic pain involves two key con- in L4 DRGs (Fukuoka et al 2000). (4) Expression of the TTX-
cepts: (1) inappropriate activity in nociceptive bers (injured resistant sodium channel Nav1.8 increases in the sciatic nerve
and uninjured) and (2) central changes in sensory processing (Gold et al 2003).
that arise from these abnormalities. To consider how these Additional evidence for a contribution of non-axotomized
mechanisms generate heightened pain we discuss in some nociceptors comes from clinical studies demonstrating that
depth the simplest of neuropathic pain models: the sequelae distal therapies are effective in neuropathic pain states. Cap-
of severing a nerve. saicin causes degeneration of the cutaneous terminals of
nociceptors that express TRPV1 (Nolano et al 1999). Cap-
Ectopic Sensitivity Develops in Injured saicin applied to the skin can alleviate the pain associated
with nerve injuries (e.g., Robbins et al 1998). This clinical
effect can be understood only by invoking a role of cutane-
When a nerve is severed, the nociceptors are also severed. The ous nociceptors that survive the injury. Moreover, since the
injured (transected) nociceptors could in principle function toxicity of capsaicin appears to be restricted to the skin, it is
abnormally at the site of nerve transection (the neuroma). the cutaneous terminal of the nociceptor that must be gen-
Indeed, abnormal spontaneous activity has been observed in erating pain.
A and C bers originating from a neuroma (see Chapter 64).
Given that a substantial proportion of C-ber afferents are Wallerian Degeneration
nociceptors, it is likely that this spontaneous activity is in fact
and Neuropathic Pain
occurring in nociceptive afferents. In patients with a painful
neuroma and hyperalgesia, locally anesthetizing the neuroma When the L5 spinal nerve is cut, the axons distal to the cut
may eliminate the pain and hyperalgesia (Gracely et al 1992). undergo wallerian degeneration. In the peripheral nerve, axons
Thus, ongoing activity arising from nociceptive bers in the from intact nerve roots are in close proximity to degenerating
neuroma contributes to the ongoing pain and hyperalgesia axons and thus are exposed to diffusible factors released into
after nerve injury and may contribute to phantom limb pain the endoneurial space or at the nerve terminals. These fac-
(see Chapter 67). tors could be derived from Schwann cells or macrophages and
Ectopic mechanical sensitivity also develops in experimen- could affect nociceptive terminals directly or indirectly by an
tal neuromas. Tapping at the site of a neuroma leads to a alteration in the cell bodies of nociceptors. As illustrated in
neural response. This may account for the observation that Figure 1-20, wallerian degeneration may play a role in neu-
tapping on a neuroma is quite often found to be painful ropathic pain by producing sensitization of primary afferent
(Tinels sign). Supercial neuromas, which are more prone nociceptors and/or by leading to the development of central
to accidental mechanical stimulation, or neuromas that are sensitization.
in locations associated with high mechanical stress are more
likely to be painful. One strategy to alleviate neuroma pain is NOCICEPTORS AND THE SYMPATHETIC
to resect the neuroma and move the nerve to a deep location.
Since neuromas form when a nerve is cut, removing a neu-
roma in essence is a neuroma relocation operation. Neuroma Activity in nociceptors induces an increase in sympathetic dis-
relocation effectively relieves pain enduringly in at least some charge. This increased discharge is associated with the rise in
cases (Burchiel et al 1993). blood pressure in acute pain states. Usually, the converse is
not true: sympathetic activity does not affect the discharge of
nociceptive neurons. In certain patients with pain, however,
The Role of the Intact Nociceptor
nociceptors acquire sensitivity to NE released by sympathetic
Several lines of evidence suggest that uninjured, intact noci- efferents. Pain dependent on activity in the sympathetic nervous
ceptors that share the nerve of the injured bers play a role in system is referred to as sympathetically maintained pain (SMP).
neuropathic pain. Much of the evidence comes from animal SMP may or may not be an important pain mechanism
models of neuropathic pain in which the L5 spinal nerve is overall in patients, but in at least some individuals SMP
cut and ligated (Kim and Chung 1992). This injury leads to may be the driving pathophysiological basis for the pain (for
behavioral signs of hyperalgesia to mechanical and heat stim- review see Drummond 2010). SMP in particular is noted in
uli applied to the ipsilateral foot. Using this model, we have many cases of complex regional pain syndrome (reex sym-
learned the following: (1) Dorsal rhizotomy of the lesioned L5 pathetic dystrophy, causalgia). This condition is usually trig-
root does not reverse the hyperalgesia regardless of whether gered by trauma to an extremity, with varying combinations

chain induces pain in patients with causalgia (Walker and

A PNS CNS Nulson 1948, White and Sweet 1969). Also, physiological
Pain activation of sympathetic vasoconstrictor neurons leads to
Wallerian DRG
enhanced spontaneous pain and hyperalgesia in patients with
degeneration L5
Hind SMP (Baron et al 2002). Pain is increased in the majority of
paw patients with complex regional pain syndrome when sympa-
Spinal thetic nervous system activity is evoked by a loud startling
cord noise or by cooling their forehead (Drummond et al 2001).
Sensitization L4 Injection of NE around stump neuromas or in the skin of
of patients with post-herpetic neuralgia induces an increase in
spontaneous pain (Chabal et al 1992, Choi and Rowbotham
1997, Lin et al 2006). In SMP, anesthetic blockade of the
sympathetic nervous system relieves the pain and hyperalge-
sia; intradermal injection of NE into the previously hyper-
von Frey
algesic area induces pain (Ali et al 2000). NE injected into
probe normal subjects evokes little or no pain. This suggests that
SMP does not arise from too much NE, but rather from the
presence of adrenergic receptors in the skin that are coupled
B PNS CNS to nociceptors. Therefore, in SMP, the NE that is normally
Pain released from sympathetic terminals acquires the capacity to
Wallerian DRG evoke pain.
degeneration L5
paw Nerve Injury Induces Catechol
Spontaneous L4 Sensitization in Nociceptors
activity in
nociceptors Spinal
In addition to spontaneous activity, adrenergic sensitivity
L4 cord develops in nociceptors after nerve injury. In a primate model
of an L6 spinal nerve lesion (Ali et al 1999), intact nocicep-
Central tors innervating the foot exhibited spontaneous activity and
sensitization a response to the 1-adrenergic agonist phenylephrine applied
von Frey to the receptive eld. In monkeys in which no spinal nerve
lesion was applied, little or no catechol sensitivity and spon-
taneous activity were present. Using a somewhat different
Figure 1-20. Wallerian degeneration in distal nerves may account for injury model, studies in rabbits have also demonstrated cat-
the development of hyperalgesia in patients with neuropathic pain. echol sensitization of intact nociceptors after injury to com-
When a nerve is cut, the nerve bers distal to the cut undergo wallerian panion nerve bers (Sato and Perl 1991). C bers ending in a
degeneration. Adjacent uninjured bers are exposed to a dramatically altered
endoneurial environment. The inammatory milieu may include chemokines,
neuroma also display adrenergic sensitivity (e.g., Hbler et al
cytokines, and growth factors. This may lead to the development of periph- 1987). Thus adrenergic mechanisms may play a role in acti-
eral or central sensitization. A, Peripheral sensitization. Wallerian degener- vating injured nociceptors as well.
ation may lead to the sensitization of primary afferent nociceptors. Now,
mechanical stimulation of the nociceptors results in an enhanced response,
which accounts for the mechanical hyperalgesia. B, Central sensitization. 1-Adrenergic Agonists Activate
Wallerian degeneration may lead to the development of spontaneous activ- Nociceptors Leading to Central
ity in nociceptors. This spontaneous activity may produce a state of central Sensitization
sensitization similar to that described for secondary hyperalgesia (see Fig.
1-17B). Now, mechanical stimulation of low-threshold mechanoreceptors Clinical studies support the postulate that SMP arises from
activates the sensitized central pain-signaling neurons, which accounts for
the mechanical hyperalgesia. CNS, central nervous system; DRG, dorsal root
expression of -adrenergic receptors on the terminals of noci-
ganglion; PNS, peripheral nervous system. ceptors. Systemic phentolamine, an -adrenergic antagonist,
relieves pain when given to patients with SMP (Raja et al
1991). Topical application of clonidine, an 2-adrenergic
agonist, to the painful skin of patients with SMP relieved
of edema, allodynia and hyperalgesia, vasomotor and sudo- hyperalgesia in the painful area (Davis et al 1991). Activa-
motor abnormalities, and motor disturbances developing in tion of 2-adrenoceptors located on sympathetic terminals
the extremity. For SMP, procedures that interrupt the func- by clonidine blocks the release of NE. When phenyleph-
tion of the sympathetic nervous system can alleviate the pain rine, a selective 1-adrenergic agonist, was applied to the
and hypersensitivity. clonidine-treated area, pain was rekindled in patients with
SMP (Davis et al 1991). Thus, clinical data, as well as pri-
Sympathetically Maintained Pain mate physiological data, suggest that in SMP, release of NE
Is a Receptor Disorder from the sympathetic terminals activates nociceptors that
express 1-adrenoceptors. The spontaneous activity and
Clinical studies support the concept that catechol sensitiv- excitation of nociceptors by NE lead to central sensitiza-
ity may develop in nociceptors after partial nerve injury. tion. Whether a change in phenotype or some other molecu-
For example, intraoperative stimulation of the sympathetic lar change explains this nociceptor chemical sensitization is
30 Section One | Neurobiology of Pain

unanswered. Of some interest is the nding that the density Acknowledgment

of 1-adrenoceptors in the epidermis of hyperalgesic skin of
patients with complex regional pain syndrome is increased We appreciate the technical assistance of T. V. Hartke and
as measured with quantitative autoradiographic techniques Ian Suk for contributing original artwork. This work was sup-
(Drummond et al 1996). For SMP, procedures that reduce or ported by National Institute of Health grants P01 NS 47399,
eliminate excitation of 1-adrenergic receptors lessen noci- NS-14447, and NS-26363.
ceptor activity and therefore lessen the hyperalgesia. Other
potential central mechanisms that modulate nociception and The references for this chapter can be found at www
emotional responses by adrenergic facilitation of nociceptive .expertconsult.com.
transmission in the dorsal horn or thalamus and/or by deple-
tion of bulbospinal opioids have also been postulated (Drum-
mond 2010).
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Dong X, Han S, Zylka MJ, et al: A diverse family of GPCRs expressed in duction mechanisms in nociceptive primary afferents innervating monkey
specic subsets of nociceptive sensory neurons, Cell 106:619632, 2001. skin, Journal of Physiology 483:747758, 1995.
Dubin AE, Patapoutian A: Nociceptors: the sensors of the pain pathway, Weidner C, Schmelz M, Schmidt R, et al: Functional attributes discriminat-
Journal of Clinical Investigation 120:37603772, 2010. ing mechano-insensitive and mechano-responsive C nociceptors in human
Dubner R, Price DD, Beitel RE, et al: Peripheral neural correlates of behavior skin, Journal of Neuroscience 19:1018410190, 1999.
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Molecular Biology of Sensory
2 Transduction
Michael S. Gold

Pain, a sensory and emotional experience, is in the brain. As
The perception of pain arising from a noxious stimu- discussed elsewhere in this textbook, there are clearly cases,
lus starts with conversion of the energy of the stim- such as stroke, where pain can originate from within the cen-
ulus into an electrical signal in the primary afferent tral nervous system. However, the vast majority of the pain
neurons innervating the site of the stimulus. This that we experience, including chronic pain associated with
process of energy conversion is called transduction. peripheral nerve injury and inammatory disorders, arises
The three general modalities of noxious stimuli that from activity in primary afferent neurons. Moreover, the
impinge on the body are chemical, thermal, and vast majority of this activity is due to the impact of thermal,
mechanical, although each of these groups can be chemical, and/or mechanical stimuli. Afferent activity may
broken down into the specic nature of the stimulus, arise spontaneously under pathological conditions as a result
including the type of chemical, the temperature, or of changes in the relative balance of ionic currents in the mem-
unique properties of the mechanical stimulus such as brane (Liu et al 2000, 2002; Amir et al 2002), although even
torque, sheer, or stretch. Specic proteins or groups spontaneous activity may ultimately depend on membrane
of proteins called transducers underlie the process of depolarization driven by a mechanical, thermal, or chemical
transduction. There has been tremendous progress stimulus impinging on the afferent, even though the source of
over the past decade in the identication and char- the stimulus may not be readily apparent (Gold 2000a). The
acterization of transducers responsive to all three focus of this chapter is on the mechanisms that enable thermal,
modalities of stimuli. Our understanding of che- mechanical, and chemical stimuli to initiate neural activity.
motransduction has progressed the farthest with the By denition, sensory transduction is conversion of the
detailed maps that are now available for some che- energy of a stimulus into an electrical signal. For the special
motransducers of chemical binding sites and the con- senses (vision, audition, olfaction, taste), transduction occurs
formational changes in protein structure with ligand in specialized organs via cellular events specic to the stimuli
binding. Putative transducers responsive to tempera- associated with these senses. Sensory information arising from
tures ranging from noxious cold to noxious hot have the body, referred to as somatosensation, may also involve
been identied, as have transducers responsive to a specialized sense organs. For example, Golgi tendon organs
variety of mechanical stimuli, but it is now clear that and Meissners corpuscles are involved in the transduction of
still more of both types of transducers have yet to be tension on tendons and low-threshold mechanical stimuli on
identied. Although transduction of noxious stimuli glabrous skin, respectively. The primary afferents or sensory
was once thought to be an intrinsic property of noci- neurons innervating these structures tend to have rapidly con-
ceptive afferents, mounting evidence indicates that ducting myelinated axons and anatomically distinct, specialized
transduction also occurs in a variety of cells surround- endings that often incorporate non-neuronal cells (Caterina
ing the afferent terminals; we are only just beginning et al 2005). In contrast, afferents referred to as nociceptors
to tease apart the impact of the interplay between respond to noxious or potentially tissue-damaging stimuli that
these direct and indirect transduction processes. The are normally perceived as painful. Axons of these neurons tend
critical interaction between transducers and the ion to have slowly conducting unmyelinated (C bers) or thinly
channels that control the excitability of afferent myelinated (A bers) axons with peripheral terminals that are
terminals has long been appreciated. However, the not associated with specic structures or cell types (Caterina
molecular identity of many of these channels has now et al 2005). Thus, nociceptors are said to have free nerve end-
been determined. Finally, despite evidence that there ings. Although recent data, discussed below, have forced inves-
are still transducers to be identied, the contribu- tigators to rethink the contribution of other cell types to sensory
tion of many transducers to injury-induced changes transduction, an important implication of the free nerve ending
in sensitivity has now been characterized. Advances is that the molecular machinery necessary for transduction of
on all three of these fronts have suggested novel noxious stimuli must be intrinsic to the nociceptive afferents.
approaches for the treatment of pain that are being The subsequent demonstration that subpopulations of isolated
actively pursued. sensory neurons are responsive to thermal (both hot and cold)
(Cesare and McNaughton 1996; Reichling and Levine 1997;
Reid and Flonta 2001a, 2001b; Viana et al 2002; Thut et al
2003), mechanical (McCarter et al 1999, Drew et al 2004),

32 Section One | Neurobiology of Pain

and a variety of algogenic chemical stimuli (Gold and Gebhart low-threshold voltage-gated ion channel capable of pushing
2010) is consistent with the idea that transduction is an intrin- the membrane potential above the action potential thresh-
sic property of nociceptive afferents. old. That is not to say that the localization of ion channels is
The available evidence indicates that the resting membrane not critical for the ultimate success (i.e., generation of action
potential of nociceptive afferents is negative to 40 mV, with potentials) of transduction via all three mechanisms, but this
values at the cell body ranging between 50 and 75 mV is particularly true for Cl because of the unique regulation
(Baccaglini and Hogan 1983, Gold et al 1996). Evidence from of Cl in sensory neurons. There is evidence in some neurons
study of the putative nociceptive afferent somata in vitro sug- that the concentration of intracellular Cl may be high enough
gests that the action potential threshold is relatively high at that the Cl equilibrium potential is above the action potential
greater than 35 mV (Gold et al 1996; Petruska et al 2000, threshold. Consequently, activation of a Cl channel in these
2002; Flake et al 2005; Harriott et al 2006; Harriott and neurons, such as bradykinin-induced activation of the Ca2+-
Gold 2009b). Thus, because action potential generation is dependent Cl channel TMEM16, may result in a generator
necessary for propagation of sensory information to the cen- potential sufcient for generation of an action potential (Liu
tral nervous system, transduction of nociceptive stimuli must et al 2010). Though depolarized relative to the resting mem-
ultimately result in membrane depolarization. The membrane brane potential in almost all sensory neurons, the Cl equilib-
depolarization resulting from a transduction event is called a rium potential is still below the action potential threshold in
generator potential. many sensory neurons. However, if there are low-threshold
A generator potential can be initiated in three primary voltage-activated channels such as the T-type Ca2+ channel
ways. The rst and most direct way involves the opening of Cav3.2 in close association with Cl channels, activation of a
an ion channel with an ion permeability ratio such that the Cl channel may still be sufcient for action potential genera-
equilibrium potential for the net charge movement through tion even if the Cl equilibrium potential is below the action
the channel is depolarized to the action potential threshold. potential threshold (see Fig. 2-1).
In this case, sufcient activation of this ion channel will drive Many chemical stimuli act on the G proteincoupled recep-
the membrane potential above threshold and thereby result in tors (GPCRs) expressed on nociceptors. In these cases, as dis-
an action potential that can be propagated toward the central cussed below, subsequent intracellular signaling cascades are
nervous system. Activation of the transient receptor poten- needed to modify ion channel activity and drive initiation of
tial vanilloid type 1 (TRPV1) channel is an example of such the generator potential.
a transduction mechanism. As discussed below, the TRPV1
channel is activated or opened by thermal (heat) stimuli CHEMO-, THERMO-, AND
(Caterina et al 1997), as well as by a variety of chemical stim-
uli (Caterina et al 2005). It is a non-selective cation channel
that is permeable to Ca2+, Na+, and K+ such that the equilib- Transducers are often categorized according to the stimuli
rium potential, or the potential at which there is no net ux of to which they are responsive. This is a useful way to think
charge, is approximately 0 mV for this channel. Because this about transducers, particularly in the context of a particu-
equilibrium potential is above the action potential threshold, lar type of pain or altered sensitivity such as cold allodynia
activation of enough TRPV1 channels can ultimately result in or heat hyperalgesia, because it is reasonable to assume that
action potential generation (Fig. 2-1). these types of pain are due to afferent activity evoked with
A second mechanism underlying the generator potential a specic stimulus. However, many, if not most of the puta-
involves the closing of a channel responsible for a hyper- tive thermo- and mechanotransducers respond to more than
polarizing current. K+ channels are the only channels capa- one stimulus modality and are therefore said to be polymodal.
ble of contributing such a current in nociceptive afferents. Given evidence that a variety of transducers are present and
This is because of the distribution of ions inside and out- functional in non-neural tissue, it is also reasonable to cat-
side nociceptive afferents. That is, interstitial uid has a egorize transducers according to whether they are intrinsic or
relatively high concentration of Na+, Ca2+, and Cl and a extrinsic to the primary afferent. Furthermore, given evidence
low concentration of K+. In contrast, in nociceptive affer- that at least one putative transducer (TRPV1) may be present
ents, the intracellular concentration of K+ is high, that of and functional on subcellular organelles (Castro et al 2009),
Cl is relatively high (Rocha-Gonzalez et al 2008), and that it is at least worth considering transducer localization despite
of Na+ and Ca2+ is low. Closing of a K+ current is clearly evidence that the vast majority of transducers are membrane
an indirect mechanism of sensory transduction since it will bound. Nociceptive afferents and consequently transducers
result in a generator potential only if a resting depolarizing are present throughout the body. Although a pinprick and
current is simultaneously active with the hyperpolarizing noxious stretch are both mechanical stimuli, visceral afferents
K+ current. Relatively high K+ conductance in the face of such as those innervating the colon are far more sensitive to
relatively low Na+ conductance will still enable the neuron stretch (i.e., colon distention) than other forms of mechani-
to maintain a resting membrane potential in the expected cal stimuli (Ness and Gebhart 1990), whereas pinprick is a
range. If the decrease in K+ channels is sufcient in such a highly effective stimulus for activating nociceptive afferents
neuron, the result will be a generator potential capable of innervating the skin (Caterina et al 2005). Consequently, it is
driving the membrane potential above the action potential important to consider the nature of the stimulus and the tissue
threshold (see Fig. 2-1). being affected. Finally, even though a number of chemotrans-
The third mechanism underlying a generator potential is ducers are activated by noxious chemicals in the environment,
also indirect, but in contrast to the second mechanism, it is the majority, if not all, are responsive to endogenous chemi-
dependent on a relatively close association between an ion cals. Therefore, it is also important to consider the source of
channel capable of driving membrane depolarization and a the stimulus.

A +10
V (mV)

-30 APThresh


B +60 Echannel

V (mV)

-30 APThresh


C +60
V (mV)


Cl- K+

Figure 2-1. At least three mechanisms underlie the initiation of a generator potential. A, One involves activation of an ion channel such as transient
receptor potential vanilloid 1 (TRPV1) with a permeability ratio such that the equilibrium potential for ions owing through the channel (Echannel) is above
the action potential threshold (APThresh). Sufcient activation of such a channel will drive the membrane above the AP threshold. This generator potential is
passively propagated to an action potential initiation site with a high density of voltage-gated Na+ channels. Decay of the generator potential is determined
by the passive electrophysiological properties of the nociceptor terminal, which is dynamically inuenced by the density, distribution, and activity of leak K+
channels such as the two-pore K+ channels TREK-1, TASK, and others. If the generator potential is above the AP threshold at the spike initiation site, an AP
will be generated that is propagated toward the central nervous system. B, Another mechanism involves closing of a K+ channel such as a two-pore K+ chan-
nel. In this scenario there must be at least one other channel open, such as a persistent Na+ channel with an E channel above the AP threshold. Closing the
K+ channels results in an increase in the relative permeability of the membrane for the depolarizing current, which may be sufcient to drive the membrane
potential above the AP threshold. As in A, this generator potential must also be passively propagated toward the spike initiation zone. C, A third mechanism
involves activation of a channel that has an equilibrium potential threshold. This appears to be the case for GABAA receptors in some nociceptive afferents. If
this channel is close to a low-threshold voltage-activated channel, such as a low-voltage-activated Ca2+ channel, the depolarization driven by activation of the
transducer may be sufcient to activate the voltage-gated channel and push the membrane potential above the AP threshold. As in A, this generator potential
must also be passively propagated toward a spike initiation site. GABA, -aminobutyric acid. leak K+ channels; voltage-gated K+ channels; voltage-gated
Na2+ channels.

receptor, for the chemical stimulus and is also an ion chan-
Of the three primary modalities of somatosensory stimuli, the nel. Binding of the chemical to the receptor drives a confor-
process of chemotransduction is the most well understood. mational change in the transducer protein that opens the ion
Specicity for one chemical over another is achieved through channel (e.g., see Mayer 2011). Thus, these transducers are
binding sites in the transducer that are unique, or at least rela- also referred to as ionotropic receptors (Fig. 2-2). This is
tively so, for a particular chemical. In the most direct form the most rapid form of chemical transduction, with signal-
of chemotransduction, the transducer has a binding site, or ing possible on the microsecond time scale. There is also an
34 Section One | Neurobiology of Pain

particularly those responsible for action potential initiation, is a

Metabotropic receptor Ionotropic receptor
critical determinant of whether a generator potential will result
Na+ in an action potential. To add to the complexity of metabo-
Na+ tropic receptor signaling, there is evidence that second-messen-
ger coupling is dynamic and changes in response to a number
of different conditions, including hormonal status (Dina et al
ATP 2001) and history of prior stimulation (Parada et al 2005).
Gq Furthermore, it is dependent not only on the appropriate local-

ization of transducers and targeted ion channel but also on
the appropriate cellular signaling machinery. Consequently,
metabotropic receptor activation may not always result in a
generator potential. Second, allosteric modulation of che-
Na+ motransducers, where a second chemical binding site is located
at a site different from that of the chemical that activates the
receptor, is common and can result in profound changes in che-
motransducer activity. An extreme example is the N-methyl-
d-aspartate (NMDA) type of ionotropic glutamate receptor:
for glutamate to activate the receptor, it must also be bound
to glycine (Ren and Dubner 1999, Dubner 2004, Salter 2005).
Figure 2-2. Ionotropic receptors are directly coupled to ion channels. Third, a number of chemotransducers may be activated by
The purinergic P2X3 receptor is composed of three subunits. Binding of several distinct chemicals. In the case of TRPV1, a transducer
adenosine triphosphate (ATP) drives a conformational change in the subunit
assembly that leads to opening of an Na+ channel. The result is rapid mem- activated by protons and capsaicin (the pungent component
brane depolarization. Metabotropic receptors initiate a second-messenger of chili peppers), the binding sites or receptors for these com-
cascade. The purinergic P2Y2 receptor is a G proteincoupled receptor able pounds are on distinct parts of the protein (Gavva et al 2005).
to drive an action potential. The ion channel coupled to P2Y2 receptors has
yet to be identied, but as a Gq-coupled G proteincoupled receptor, it could
drive the activation of phospholipase C, which has been shown to activate
Ionotropic Receptor Families
transient receptor potential vanilloid 1 (TRPV1), a non-selective cation chan- Acid-Sensing Ion Channels
nel, secondary to cleavage of phosphatidylinositol 4,5-bisphosphate (PIP2). Ionotropic receptors are generally classied according to
their structure and genetic homology. The acid-sensing ion
channels (ASICs) are, as their name implies, activated by
indirect form of chemotransduction whereby the conforma- extracellular protons, although this is true for only three
tional change in the transducer driven by chemical binding of the four genes encoding ASIC channel subunits (ASIC1,
results in the activation of an intracellular signaling cascade. 3, and 4) since ASIC2 does not appear to be activated by
These transducers are referred to as metabotropic receptors protons (Lingueglia 2007). All four subunits are detected in
(see Fig. 2-2). This form of chemical transduction is slower sensory neurons (Alvarez de la Rosa et al 2002, Hughes et al
and occurs on a time scale of milliseconds to minutes. Gua- 2007, Bohlen et al 2010), including the two splice variants
nine nucleotidebinding proteins, or GPCR receptors, are by of ASIC1 (1a and 1b) and ASIC2 (2a and 2b). The ASICs are
far the most common type of metabotropic receptor, with trimeric proteins with homology to the epithelial Na+ chan-
the type of G protein being responsible for both initiation of nel (ENaC)/degenerin family that can form homomeric or
the cellular signaling cascade and the type of cascade initi- heteromeric channels (Qadri et al 2012). ASIC3 was origi-
ated (Bunnett and Cottrell 2010). Additional metabotropic nally thought to be specic to dorsal root and trigeminal
receptors found in sensory neurons include receptors bearing ganglion neurons (Chen et al 1998), where it is enriched in
intrinsic protein tyrosine kinase domains (i.e., Trk receptors), nociceptive afferents, but it has subsequently been shown to
receptors that associate with cytosolic tyrosine kinases (i.e., be more widely expressed (Sanchez-Freire et al 2011, Sole-
nontyrosine kinase receptors such as cytokine receptors, Magdalena et al 2011). It is the most sensitive to protons
integrins), and protein serine/threonine kinases (i.e., trans- activated by a decrease of less than 0.2 pH unitsand this
forming growth factor- [TGF-] receptors) (see Gold 2005 sensitivity is dramatically enhanced with lactate (Immke and
for review). This second form of signaling is very widespread McCleskey 2001). Intense muscle use produces lactic acidas,
and responsible for changes in the regulation of a variety of a metabolic produce that is thought to contribute to exercise
cellular processes, including ion channel properties (Fitzger- and ischemic muscle pain. Thererfore, ASIC3 is one of sev-
ald et al 1999), cellular properties such as the regulation of eral transducers present in muscle afferents that may also be
intracellular Ca2+ (Werth et al 1996) and neurite extension referred to as metaboreceptors (Molliver et al 2005). ASIC3
(Yasuda et al 1990, Jones et al 2003), and gene expression is enriched in specic subpopulations of afferents, including
(Huang and Reichardt 2003). Second-messenger signaling is those innervating the heart (Benson et al 1999) and dura
complex with multiple points of convergence and interaction (Yan et al 2011), where it has been suggested to contribute
(Gold and Gebhart 2010). However, to keep this chapter trac- to the pain associated with coronary ischemia and migraine,
table, I will consider only metabotropic receptormediated respectively. Evidence from null mutant mice suggests that
transduction events that are coupled to an ion channel that ASIC3 contributes to hyperalgesia of an inamed muscle
may initiate a generator potential. (primary hyperalgesia) whereas ASIC1 contributes to the
At least three additional factors have an impact on the ef- hyperalgesia observed at sites distant from the inamed mus-
cacy of chemoreceptor signaling. First, the spatial distribution cle (secondary hyperalgesia) (Walder et al 2010), although
of transducers relative to other ion channels in the membrane, the details underlying the basis for this distinct pattern have

yet to be fully claried. Recent data indicating that venom largest source of serotonin in the body, it should not be sur-
from the western coral snake can directly activate ASIC1 prising that this receptor plays an even more important role in
(Bohlen et al 2010) further support a role for this subunit visceral pain. In fact, several 5-HT3 receptor antagonists have
in the response to pain-producing stimuli and suggest that been approved for use in treating the pain associated with
these channels are responsive to a wider variety of stimuli irritable bowel and other visceral pain syndromes (Fayyaz and
than originally thought. The observation that the pH sensi- Lackner 2008).
tivity of ASIC2a was dramatically increased by coral snake Unlike the nAChRs and 5-HT3 receptors, which have ion
venom also led to the suggestion that this subunit may func- channels permeable to Na+, K+, and to varying degrees, Ca2+,
tion as a coincidence detector for as yet to be identied com- GABAA receptors have an ion pore selective for anions (pri-
pounds. Along these same lines, recent evidence suggests marily Cl and to a less degree HCO3) (Michels and Moss
that ASIC3 and P2X5 may act as coincidence detectors since 2007, Picton and Fisher 2007). Like nAChRs and 5-HT3
binding of adenosine 5-triphosphate (ATP) to P2X5 dramat- receptors, GABAA receptors may exist as homomeric or het-
ically increases the sensitivity of ASIC3 to protons (Birdsong eromeric proteins. The homomeric proteins are composed of
et al 2010). one of the three subunits (originally called GABAC recep-
tors) and have been most studied extensively in the retina
Cys-Loop Family of Ligand-Gated Ion Channels (Qian 19952005). Recent evidence suggests that subunit
ACh/5-HT3/GABAA. One of the larger families of ligand- containing receptors are present in sensory neurons. However,
gated ion channels is the Cys-loop family, so named because heteromeric GABAA receptors are far more common through-
of the characteristic loop in the extracellular N-terminal out the nervous system, including sensory neurons. Although
domain of the subunit formed by a disulde bond between 19 subunits of the GABAA receptor have been identied, the
two cysteine (Cys) residues (Tsetlin et al 2011). Members of number of possible receptors is constrained by a subunit stoi-
three of the four major subfamilies of Cys-loop receptors are chiometry that consists of two subunits, two subunits,
present in sensory neurons. These include nicotinic acetylcho- and one of the remaining seven non- subunits. GABAA recep-
line receptors (nAChRs), serotonin type 3 (5-HT3) receptors, tor subunit composition determines the pharmacological and
and type A -aminobutyric acid (GABA) receptors (GABAA). biophysical properties of the receptor, as well as its cellular
All Cys-loop receptors contain ve subunits, which may be distribution (Michels and Moss 2007).
homomeric or heteromeric, depending on the receptor sub- Given that GABAA receptors underlie the vast majority of
type and subunit composition. fast inhibitory synaptic transmission in the adult central ner-
Both homomeric (7; Shelukhina et al 2009) and hetero- vous system, it may be surprising to nd these receptors among
meric (36, 24; Xiao et al 2002, Rau et al 2005, Spies et al a list of chemotransducers. However, because, as noted above,
2006) nAChRs composed of two and three subunits are the concentration of intracellular Cl is maintained at levels
present in sensory neurons, with evidence that both forms considerably higher in nociceptive afferents than in neurons
contribute to nociceptive processing (Carstens et al 1998, in the central nervous system (Rocha-Gonzalez et al 2008),
Schmelz et al 2003). Although there are several potential non- GABAA receptor activation results in membrane depolariza-
neural sources of acetylcholine (ACh) in the periphery, it is tion in nociceptive afferents (Price et al 2009), which may still
important to note that ACh levels are increased in inamed be inhibitory in the absence of tissue injury. However, fol-
tissue (Wessler et al 2003, Gahring et al 2010). Furthermore, lowing tissue injury, GABAA receptor activation may result
peripheral administration of ACh- or nAChR-selective ago- in action potential generation in nociceptive afferents (Willis
nists results in burning pain (although recent evidence suggests 1999). This can occur at the central terminals of nociceptive
that at least some of the pain associated with nicotine may be afferents, a process referred to as the dorsal root reex. More
due to activation of TRPA1 (Talavera et al 2009). Interest- importantly in the context of the present discussion, GABAA
ingly, recent evidence also suggests that the relative contribu- receptor activation in the periphery can excite nociceptive
tion of nAChR subtypes to peripheral pain may depend on afferents (Carlton et al 1999, Carr et al 2010). It should be
the target of innervation. That is, 7 nAChRs appear to sup- noted that although there do not appear to be sources of
press activity in colonic dorsal root ganglion (DRG) neurons peripheral GABA necessary to achieve the concentrations
(Abdrakhmanova et al 2010), whereas the burning pain asso- needed for activation of low-afnity synaptic receptors, recent
ciated with the application of nAChR agonists to the skin is evidence suggests that high-afnity receptors, which may be
probably mediated by heteromeric receptors (Carstens et al activated by GABA concentrations close to the resting levels
1998, Schmelz et al 2003). observed in extracellular uid, are present in sensory neurons
The 5-HT3 receptor is the only ionotropic serotonin recep- (Lee et al 2012). Thus, even though there is evidence that a
tor. It may exist as a homomeric receptor composed of ve shift in GABAA signaling in the spinal cord contributes to both
5-HT3A subunits or as a heteromeric receptor composed of the initiation and maintenance of inammatory hypersensi-
a 5-HT3A subunit with one of the other four 5-HT3 subunits tivity, high-afnity GABAA receptors in the periphery may
(5-HT3B3E) (Thompson and Lummis 2007). It was originally also contribute to ongoing afferent drive in the presence of
thought to have a relatively limited role in nociception because inammation.
of its expression pattern in afferents with a medium to large
cell body diameter (Tecott et al 1993). Subsequent analysis, Glutamate Receptors
however, suggested that this receptor is critical for both sero- Ionotropic glutamate receptors play a critical role in fast
tonin-induced pain and, more importantly, full expression of excitatory synaptic transmission in the central nervous sys-
the second phase of pain behavior in the formalin test (Zeitz tem and are therefore generally studied in the context of
et al 2002), a behavior thought to reect spontaneous inam- synaptic transmission. These receptors have historically
matory pain. Given that the gastrointestinal (GI) tract is the been classied according to their response to three selective
36 Section One | Neurobiology of Pain

agonists: -amino-3-hydroxy-5-methyl-4-isoxazolepropionic Purinergic ReceptorsP2X

acid (AMPA), kainate, and NMDA (Mayer 2011). Subse- Ionotropic purinergic, or P2X, receptors are activated by
quent analysis has indicated that these receptors are com- ATP. The functional receptor is a trimer. Seven subunits
posed of heteromeric combinations of four subunits, with have been identied, P2X17; all but P2X6 can form func-
AMPA receptors being composed of GluR14, kainate recep- tional homomers, and each appears to be able to form a het-
tors being composed of GluR57 (GluK13) and/or KA12 eromeric protein with at least one other subunit (Burnstock
(GluK45), and NMDA receptors being composed of a 2006, Jarvis and Khakh 2009). At least six, if not all seven,
combination of NR1, NR2AD, and/or NR3AB. All three subunits are present in sensory neurons, with all but P2X4
types of receptors are present and functional in primary affer- being differentially distributed among subpopulations of
ent neurons (Miller et al 2011). Interestingly, even though DRG neurons (Kobayashi et al 2005). P2X3, which forms
these receptors are present on the central terminals of pri- a heteromer with P2X2, has been the most extensively stud-
mary afferents, where they appear to contribute to synaptic ied member of this family with respect to nociceptor acti-
transmission in the spinal cord, they are also present in the vation (Jarvis 2003). This subunit was originally shown to
periphery, where they can drive action potential generation be enriched in a subpopulation of neurons with a small cell
(Cairns et al 1998, 2001b; Lam et al 2009a, 2009b) and body diameter that did not express the neuropeptides sub-
pain (Cairns et al 2001a). There are a number of potential stance P or calcitonin generelated peptide (CGRP) (Brad-
sources of peripheral glutamate, including the afferent itself, bury et al 1998), the so-called non-peptidergic afferents.
where peripherally released glutamate could serve as a form of Although the distribution of P2X3 receptors among specic
feedback excitation to amplify injury-induced activation of subpopulations of sensory neurons was subsequently shown
nociceptive afferents. to depend on the target of innervation (e.g., see Ambalava-
nar et al 2005), pharmacological and molecular biological
HCN Channels analysis conrmed that this subunit plays a dominant role
Hyperpolarization-activated, cyclic nucleotidegated (HCN) in mediating the nociceptive response to the application of
ion channels are not typical chemotransducers since they are ATP, as well as the response to a variety of noxious stimuli
not directly activated by extracellular ligand binding (Wick- applied to various tissues (Jarvis 2003). Interestingly, this
enden et al 2009). Furthermore, because these non-selective subunit appears to mediate the activation of nociceptive
cation channels are activated by membrane hyperpolarization afferents observed following damage to neighboring cells
and close with membrane depolarization, their biophysical (Cook and McCleskey 2002), thus making this transducer
properties argue against a role in the initiation of a generator a critical player in the initial pain observed in response to
potential capable of driving the membrane above the action tissue injury. As noted above, more recent work has high-
potential threshold. Under resting conditions, these channels lighted a potential role for P2X5 in the sensitization of ASIC
are activated only during the increase in membrane potential currents in sensory neurons and consequently the pain asso-
associated with the after-hyperpolarization that follows an ciated with muscle ischemia (Birdsong et al 2010).
action potential, where they provide a depolarizing drive for
subsequent spike initiation (Ingram and Williams 1994). There Transient Receptor Potential Channels
are four HCN family members (HCN14), which consistent The TRP channels involved in chemotransduction come
with their homology to Kv family members, form homomeric from a large family of ion channels that encompass eight
tetramers (Wickenden et al 2009). mRNA for all four HCN subfamilies ranging from TRPA (for ankyrin) to TRPV (for
channels is detectable in sensory neurons, with HCN1 being vanilloid), with TRPC (for canonical), TRPM (for mela-
differentially distributed in large- and small-diameter neurons statin), TRPML (for mucolipins), TRPP (for polycystins),
and HCN3 enriched in small-diameter neurons (Chaplan et al and TRPN (for NO-mechanopotential C) in between (Nilius
2003, Kouranova et al 2008). and Owsianik 2011). Unifying features of this family include
These channels have been included in the list of chemotrans- a channel protein formed from four subunits, each with a
ducers for several reasons. The voltage dependence of channel structure analogous to that for voltage-gated K+ ion channel
activation is regulated by intracellular cyclic adenosine mono- subunits with a six-transmembrane segment and a pore loop
phosphate (cAMP) such that an increase in cAMP drives a between transmembrane segments 5 and 6. Specic to TRP
depolarizing shift in the voltage dependence of channel acti- channels are ankyrin domains on the intracellular N-terminus
vation. This shift can be sufciently large that HCN channels and proline-rich domains on the intracellular C-terminus. All
contribute to the depolarization of resting membrane potential TRP family members form Ca2+-permeable cation channels.
and, more relevantly, to a depolarizing drive that facilitates Many of the family subunits have a voltage sensor in segment
action potential generation (Emery et al 2011). The channel 4 and consequently exhibit voltage-sensitive properties. As
is also a putative target for a number of metabotropic recep- discussed below, several of the channels are activated by dif-
tors coupled to second-messenger pathways that result in an ferent stimulus modalities, with the biophysical properties of
increase in cAMP. There is an increase in HCN current den- the channel activity appearing to depend on how the chan-
sity in large-diameter neurons following traumatic peripheral nel is activated. For example, capsaicin-induced activation
nerve injury, where the increase appears to be responsible for of TRPV1 desensitizes in the presence of extracellular Ca2+,
ectopic activity (Chaplan et al 2003). Recent evidence from whereas heat-evoked activation of TRPV1 does not (Caterina
null mutant mice suggests that HCN2 in Nav1.8-expressing et al 1997). The channels also appear to be used differen-
neurons plays a particularly important role in the generation tially across phyla. For example, TRPA1 functions as a cold
of inammatory thermal hyperalgesia, as well as peripheral receptor among other modalities of transduction in mammals
nerve injuryinduced thermal and mechanical hypersensitivity (Story et al 2003, Karashima et al 2009) but underlies infra-
(Emery et al 2011). red detection in snakes (Gracheva et al 2010). The relative

contribution of various TRP channels to nociceptive process- nociceptive behavior when administered to mice, behavior that
ing is an active area of investigation. is eliminated in TRPM3 null mutant mice (Vriens et al 2011).
TRPA1. TRPA1 was originally identied through a combined TRPM8. The discovery of TRPM8 was reported almost simul-
bioinformatic and expression strategy designed to identify taneously by two different groups that used complementary
additional TRP family members (Story et al 2003). It is the only strategies of bioinformatics (Peier et al 2002a) and expression
member of its subfamily dened by the exceptional number cloning (McKemy et al 2002) to identify novel TRP channels.
(14) of N-terminal ankyrin repeats. Although TRPA1 was rst This channel was shown to be responsive to both cooling and
thought to function primarily as a cold transducer (see below), menthol. The channel is present in a small subpopulation of
subsequent analysis has indicated that TRPA1 is responsive to non-peptidergic afferents that does not overlap with TRPV1/
a variety of noxious compounds. This list rst included allyl TRPA1-expressing neurons (McKemy et al 2002, Peier et al
isothiocyanates (i.e., mustard oil) and cannabinoids (Jordt et al 2002a). Because the sensation of menthol is not usually described
2004) and was rapidly expanded to include the pungent ingre- as painful, this transduction mechanism would generally be
dients of garlic (Bautista et al 2005), cinnamon, wintergreen grouped with those associated with the transduction of non-
oil, clove oil, and ginger (Bandell et al 2004), as well as a variety noxious stimuli. It is included here for the sake of completeness
of environmental irritants such as acrolein, CO2, and formalin and, as noted below, because of evidence that the channel con-
(McNamara et al 2007). TRPA1 is also activated by a num- tributes to the perception of cold pain (Knowlton et al 2011).
ber of endogenous mediators, including products of oxidative Interestingly, recent genome-wide association studies have
stress (Andersson et al 2008) and cyclooxygenase-dependent linked TRPM8 to migraine without aura (ref PMID:21666692
fatty acid metabolites (Materazzi et al 2008, Taylor-Clark et al and 22683712), although it remains to be determined how a
2008). TRPA1 appears to be expressed in a subset of TRPV1- polymorphism in this channel contributes to the increased risk
expressing neurons and, like TRPV1, appears to be a target of for the presence of migraine.
endogenous algogenic compounds such as bradykinin (Bandell TRPV1. The eld of sensory transduction broke open in 1997
et al 2004). There is also evidence that TRPA1 may interact with the discovery of TRPV1, a TRP channel activated by cap-
with TRPV1 at the level of a complex (Akopian 2011). As a saicin, the pungent compound in chili peppers (Caterina et al
result, activation of one channel inuences the response result- 1997). This receptor had long been sought because of an exten-
ing from activation of the other. Interestingly, despite its role in sive body of both preclinical and clinical data supporting a link
mediating the acute painful response to a variety of chemicals, between the actions of capsaicin and pain (Holzer 1991). Inter-
a gain-of-function mutation in TRPA1 is not associated with estingly, although the only sensation associated with capsaicin
ongoing pain. Rather, individuals with the TRPA1 mutation in the short term is pain (Schmelz et al 2000), in the long term,
experience episodic upper body pain triggered by fasting or treated tissue can become desensitized to subsequent noxious
physical stress (Kremeyer et al 2010). stimuli (Nolano et al 1999). Probably because of species dif-
TRPM2. TRPM2 is widely expressed throughout the body ferences in the distribution of TRPV1 among subpopulations
but is particularly enriched in immune cells such as macro- of nociceptive afferents, the modality specicity of this desen-
phages (Harteneck 2005, Jiang et al 2011). It was originally sitization appears to depend on the species being studied; it
suspected that TRPM2 would have enzymatic properties in appears to be specic to noxious heat in the mouse (Cavanaugh
addition to its putative function as a Ca2+ channel based on et al 2009), but it encompasses heat, mechanical, and possi-
the presence of a Nudix box on its C-terminus, a motif com- bly chemical stimuli in the rat, dog, and primate (Nolano et al
mon to enzymes, particularly those that degrade nucleoside 1999). Various preparations of TRPV1 agonist and admin-
diphosphates (Perraud et al 2001). It is likely that this motif istration routes are still being explored for the treatment of
serves as a binding site for adenosine diphosphate (ADP)- chronic pain (Wong and Gavva 2009, Anand and Bley 2011).
ribose, which was subsequently shown to activate the channel. A number of interesting features of TRPV1 have been
It was soon realized, however, that TRPM2 plays a signicant revealed since its original discovery. As discussed below, it is
role in mediating the cellular response to stress since it is acti- not just a receptor for capsaicin but is activated by noxious
vated by reactive oxygen species such as hydrogen peroxide heat and plays a critical role in the manifestation of thermal
(Takahashi et al 2011). The channel has recently been shown hyperalgesia (Caterina et al 2000). In addition to capsaicin,
to be present in sensory neurons, where it enables sensitivity to TRPV1 is responsive to a number of different pungent com-
hydrogen peroxide (Naziroglu et al 2011). Recent data indi- pounds found in plants, including resiniferatoxin, piperine,
cate that the channel plays a prominent role in facilitating the and camphor (Tominaga et al 1998), as well as endogenous
inammatory response to infection (Yamamoto et al 2008) mediators such as protons (though with considerably lower
and is likely to contribute to inammatory hypersensitivity. potency than ASIC3) and lipids (e.g., oxidized linoleic acid
However, though present in sensory neurons (Naziroglu et al metabolites; Patwardhan et al 2009, 2010). There is evidence
2011, zgl and Naziroglu 2012), the pro-nociceptive role that phosphatidylinositol 4,5-bisphosphate (PIP2) can both
of this channel is likely to be indirect via facilitation of the activate and inhibit TRPV1 (Vriens et al 2009). In a model
release of chemokines such as CXCL2 from immune cells and in which PIP2 is inhibitory, it was proposed that algogenic
microglia. compounds such as bradykinin are able to activate TRPV1
TRPM3. TRPM3 is another member of the melastatin sub- subsequent to the activation of phospholipase C, which frees
family of TRP receptors implicated in nociception. This TRP TRPV1 from inhibition following PIP2 hydrolysis (Prescott
channel is expressed in a variety of different tissues, including and Julius 2003). The channel is a target for a number of dif-
a relatively broad population of sensory neurons (Vriens et al ferent protein kinases, thereby resulting in dynamic regulation
2011). The most potent known agonist for TRMP3 is preg- of channel properties and membrane distribution (Gold and
nenolone sulfate. Although this compound acts at a number Gebhart 2010). Channel translation and expression are also
of receptors and ion channels, it has been shown to induce dynamically regulated and enable the channel to contribute to
38 Section One | Neurobiology of Pain

both the initiation and maintenance of persistent pain. Pro- Metabotropic Receptors
longed activation of the receptor results in a process referred Seemingly endless lists of metabotropic receptors have been
to as pore dilation, where the size of the channel increases identied in sensory neurons, including a long list of GPCRs
to the point that it becomes permeable to large macromol- and neurotrophin receptors and a growing list of receptors
ecules (Chung et al 2008). A comparable process has recently for cytokines and chemokines. As discussed above, there is
been described in TRPA1 (Chen et al 2009). Although the evidence that the activity of a number of chemotransduc-
physiological consequences of this process have yet to be fully ers and ion channels may be regulated directly by activa-
elucidated, it may be possible to exploit this property for ther- tion of metabotropic receptors. For example, TRPV1 can
apeutic purposes and deliver molecules such as membrane- be activated by metabotropic receptors coupled to phospho-
impermeable local anesthetics to provide selective blockade of lipase C (Chuang et al 2001). More commonly, however,
nociceptive afferents (Binshtok et al 2007). metabotropic receptor activation results in sensitization
TRPV4. TRPV4 was rst thought to function as an osmosen- of a transducer or ion channel such that the ion channel is
sor responsive to cell swelling (see below) (Strotmann et al more readily activated by natural stimuli such as a change in
2000). Subsequent analysis has indicated that the channel is membrane potential (as for HCN channels) or temperature
also a thermosensor (see below) responsive to warming (Guler (as for TRPV1 channels). Thus, under the appropriate con-
et al 2002). Data from knockout or knockdown experiments ditions, all metabotropic receptors are theoretically capable
suggest that the channel contributes to inammatory pain and of acting as a chemotransducer. Not surprisingly, although
sensitivity (Alessandri-Haber et al 2005, 2006), particularly of there are a number of cases in which the ion channels under-
visceral structures such as the bladder (Everaerts et al 2010), lying a metabotropic receptormediated generator potential
although this appears to be due to its function as a mechano- have been identied, such as the Ca2+-dependent Cl channel
transducer (see below). Nevertheless, like other TRP channel TMEM16A (or ONO1) underlying the actions of bradykinin
family members, TRPV4 is responsive to a plant derivative, in a subpopulation of DRG neurons (Liu et al 2010), in many
as well as to articial ligands such as 4--PDD (Vriens et al cases the ion channels responsible for the generator potential
2007), thus raising the possibility that there are endogenous are unknown.
ligands that have yet to be identied. Despite the large number of metabotropic receptors
expressed in sensory neurons, the number that normally acti-
Two-Pore Potassium Channels vates nociceptive afferents is relatively small. These include
Two-pore potassium (K2P) channels are a large family of rest- the B1 and B2 receptors for bradykinin (Mense 1982), the H1
ing, or background, K+ channels that when active, inhibit cell receptor for histamine (Fu et al 1997, Jafri et al 1997, Schmelz
excitability (Honore 2007). The channels are widely distrib- et al 2003), P2Y2 receptors for ATP (Molliver et al 2002,
uted throughout the body. Family members present in sensory Stucky et al 2004), the endothelin A receptor for endothelin-1
neurons include TREK-12, TRAAK, TASK13, and TRESK, (Gokin et al 2001, Namer et al 2008), the protease-activated
although recent data suggest that additional family members receptor 2 (PAR-2) for extracellular proteases (Patwardhan
are detectable in mRNA extracted from whole ganglia (Marsh et al 2006), and IP receptors for prostacyclin (Birrell et al
et al 2012). The name for TREK-1 comes from TWIK-related 1991). Understanding signaling via metabotropic receptors in
K+ channel, where TWIK stands for a tandem of P domains in sensory neurons is complicated by two factors. First, there are
a weak inward rectier K+ channel (Patel and Honore 2001). metabotropic receptor homologues for many of the ionotropic
TREK-1 was cloned in 1996 based on homology to TWIK and receptors activated by endogenous ligands. For example,
was rst shown to be activated by arachidonic acid. TREK-2 afferents express both ionotropic and metabotropic receptors
and TRAAK (TWIK-related arachidonic acidactivated K+ for ACh (Spies et al 2006, Nandigama et al 2010), ATP (Mol-
channel) are also activated by arachidonic acid. TWIK-related liver et al 2002), glutamate (Willcockson and Valtschanoff
acid-sensitive K+ channels (TASK) are present in putative noci- 2008, Carlton et al 2009), and serotonin (Pierce et al 1996,
ceptive afferents (Rau et al 2006) and are inhibited by protons Zeitz et al 2002). The result may be a unique pattern of activ-
and serotonin (Hopwood and Trapp 2005). The S-type K2P ity as has been observed for ATP, with the initial burst of
TRESK activity appears to be regulated primarily via second- activity being mediated by the ionotropic receptor and a more
messenger signaling cascades, with activity being increased by slowly developing, longer-lasting burst being driven by the
calcineurin and inhibited by kinase activity, including protein metabotropic receptor (Molliver et al 2002) (Fig. 2-3). Sec-
kinase A, and by 1433 adaptor protein docking (Czirjak ond, the metabotropic receptors may be coupled to inhibitory
and Enyedi 2010). That inhibition of K2P activity is sufcient second-messenger pathways, which can result in yet another
to drive afferent activation is suggested by the observation pattern of activity. A variety of GPCRs are discussed further
that K2P channel blockers such as sanchool can drive activ- in Chapter 3 of this volume.
ity in isolated DRG neurons (Bautista et al 2008). Moreover,
DRG neurons from TRESK null mutant mice are hyperex- Chemotransducer Ligands
citable (Dobler et al 2007) and hyper-responsive to noxious A common feature of the chemotransducers in sensory neu-
stimuli. TRESK is also down-regulated in primary afferents rons is their ability to respond to both exogenous and endog-
following peripheral nerve injury, and this down-regulation is enous compounds. Given the array of noxious chemicals and
associated with an increase in afferent excitability (Tulleuda pathogens in the environment, it makes intuitive sense that
et al 2011). Most recently, a dominant negative mutation in the body would adapt ways of detecting the presence of these
TRESK was linked to a form of familial migraine with aura potential sources of threat or injury. Some classes of recep-
(Lafreniere et al 2010). Finally, there is evidence that TREK-1 tors for structurally conserved components of bacteria, fungi,
and -2 are down-regulated in colonic afferents in a mouse viruses, and other organisms, such as the toll-like receptors,
model of colitis (La and Gebhart 2011, La et al 2011). are specialized to detect ligands derived from exogenous

use of microdialysis probes in patients with painful oral can-

A ATP B ATP cers (Hardt et al 2011). In this case, the researchers again
reasoned that oral cancers are particularly painful because
of the compounds released within the cancer. Although this
research team has only just begun to identify the endogenous
source of this form of cancer pain, it appears to involve an
increase in proteolytic activity that drives the activation of
PARs (Lam and Schmidt 2010). A third example involves a
screen of toxins associated with intense pain in humans. This
me-ATP me-ATP led to the discovery of a toxin in western coral snake venom
that acts on ASIC channels as described above (Bohlen et al
40 mV

2010). This rst example highlights the possibility that trans-

duction of any stimulus may involve a multiple-step process

1 nA
10 s whereby the initial stimulus, such as heat or a bacterial cell
0.6 s wall, results in the activation of another cell type, such as a
resident immune cell in the case of the bacteria, that releases
the chemical ultimately responsible for the generator potential
in sensory neurons.

The Molecular Thermometer (TRPA1TRPV2)
The cloning of TRPV1 was not just a watershed moment
for the understanding of chemotransduction in nocicep-
Figure 2-3. Action potentials (A) and currents (B) evoked in a sen- tive afferents; it also facilitated the understanding of ther-
sory neuron by adenosine triphosphate (ATP) and its analogues. A motransduction as well: TRPV1 was not only the capsaicin
single application of ATP evoked two series of action potentials: a brief train receptor but was additionally a thermotransducer activated
occurred immediately after the application of ATP, and then a much lon- by noxious heat (Caterina et al 1997). Within 6 years of
ger train occurred after a delay and then persisted for many seconds after
removal of ATP. Application of alpha-beta methylene ATP (me-ATP),
the cloning of TRPV1 six different TRP channels had been
which selectively stimulates sensory neuron ATP-gated ion channels (P2X identied that together had the biophysical properties neces-
receptors), evoked the initial train of action potentials but not the prolonged sary to build a molecular thermometer that spanned the full
one. Application of uridine triphosphate (UTP), which activates G protein range of human thermosensory perception (Fig. 2-4). TRPA1
coupled ATP receptors (P2Y), evoked the delayed, persistent train but not the was found to be a transducer for noxious cold that encodes
rapid, brief one. ATP and me-ATP both evoked the large currents typical
of P2X3 channels, but UTP evoked only a very small inward current; KCNQ drops in temperature from approximately 18 to 4C (Story
has been shown to underlie much of this current. (Reproduced from Molliver et al 2003). TRPM8 had the properties of a cool receptor
DC, Cook SP, Carlsten JA, et al 2002 ATP and UTP excite sensory neu- that was responsive to small decreases in temperature lower
rons and induce CREB phosphorylation through the metabotropic receptor, than 30C (McKemy et al 2002). TRPV3, though present in
P2Y2. European Journal of Neuroscience 16:18501860. Copyright 2002
with permission from Blackwell Publishing Ltd.)
keratinocytes rather than sensory neurons, was responsive to
innocuous increases in temperature above 37C (Peier et al
2002b, Xu et al 2002). TRPV4 was also activated by innocu-
sources. Many of these receptors, including 7 of the 13 known ous warming and was clearly expressed in sensory neurons
toll-like receptors, are present in sensory neurons (Ochoa- (Guler et al 2002). TRPV1 was responsive to noxious heat
Cortes et al 2010), and although the second-messenger path- with a threshold for activation roughly comparable to that
ways activated by these receptors could result in a generator associated with a heat pain threshold (Caterina et al 1997).
potential, these receptors appear to be responsible primarily Finally, TRPV2 was responsive to heat with a threshold for
for afferent sensitization rather than activation (e.g., see Dio- activation (>48C) close to that associated with heat pain tol-
genes et al 2011). On the other hand, a number of chemotrans- erance in psychophysical studies (Caterina et al 1999). The
ducers are clearly specialized to detect endogenous signaling observation that TRPM8, TRPV4, TRPV1, and TRPV2 are
molecules, an extreme example being the glutamate receptors present in different populations of neurons was consistent
specialized to subserve fast synaptic transmission. The TRP with in vivo single-unit electrophysiological and psychophysi-
channels are prime examples of receptors with the capacity cal data (Bessou and Perl 1969, Iggo 1969, Hensel and Iggo
to respond to both exogenous and endogenous compounds. 1971, Darian-Smith et al 1973, Dubner et al 1975, LaMotte
It should therefore not be surprising that identication of and Campbell 1978, Campbell and LaMotte 1983, Treede
endogenous and exogenous ligands for chemotransducers in et al 1995) and was used to provide compelling support for
sensory neurons is an active area of investigation. Notable in the argument that a population code (i.e., activity in differ-
this regard are the creative strategies used. In one compelling ent populations of afferents) is used for thermosensation and
example, researchers reasoned that the intense and prolonged that there was a labeled line, at least from the periphery,
pain associated with a burn injury may be due to mediators for heat pain. Furthermore, the overlap between TRPV1 and
released in response to the heating of tissue. This led to the TRPA1 (Story et al 2003) was used to explain the psycho-
discovery of oxidized linoleic acid metabolites, which turned physical observation that noxious cold is perceived as burn-
out to be potent endogenous agonists for TRPV1 (Patward- ing pain. This idea has proved overly simplistic, however, as
han et al 2009, 2010). A second compelling example is the discussed below.
40 Section One | Neurobiology of Pain

K2P Channel



N N N N N N domain
0 10 20 30 40 50 60
Temperature (C)

Temperature range <17C around 826C >27C >31 or 39C >43C >52C

Agonists AG-3-5 (lcilin) Menthol N/A N/A Capsaicin N/A

Mustard oil AG-3-5 (lcilin) Resiniferatoxin
Tetra-hydro Eucalyptol Anandamide
cannabinol Protons

Tissue distribution Sensory neurons Sensory neurons Sensory neurons Sensory neurons Sensory neurons Sensory neurons
Prostate Prostate epithelia Kidney Keratinocytes Bladder Brain
Various cancers Keratinocytes Spleen
Hypothalamus Intestine
Hair cells
Merkel cells

Figure 2-4. Thermosensitive channels respond to a wide range of temperatures. This diagram depicts mammalian channels that have been demon-
strated or proposed to underlie the neural response to thermal stimuli, arranged according to their temperature response proles when examined in heterolo-
gous expression systems. Listed below each channel are their reported thermal thresholds and the range of temperatures to which they respond. Recent data
suggest that there may be additional channels that contribute to thermosensation. Most problematic is evidence in support of a role for TRPV2 in thermo-
sensation since null mutant mice have no detectable thermal phenotype. Also problematic is TPRA1, which clearly functions as a thermoreceptor for noxious
cold in heterologous systems and in isolated sensory neurons but appears to contribute to the response to noxious cold only in the presence of tissue injury.
Additional channels have also been identied that appear to contribute to thermosensation. These include the two-pore K+ channels, TREK-1, TREK-2, and
TRAAK, which are activated at between approximately 28 and 42C. This property enables these channels to contribute to the response to both warming (via
inhibition of afferent activity) and cooling (via a decrease in inhibition). TRPM3 has a relatively low threshold for activation (30C) but appears to contribute
to the response to noxious heat. Finally, TRPC5 is activated with decreases in temperature from 37 to 25C and may contribute to the response to cooling.
(Modied from Jordt SE, McKenny DD, Julius D 2003 Lessons from peppers and peppermint: the molecular logic of thermosensation. Current Opinion in
Neurobiology 13:487492. Copyright 2003 Elsevier Ltd.)

TRPA1. Concerns over the molecular thermometer model conrmed the negative behavioral data obtained in TRPA1
were raised almost immediately, with some of the most con- null mutant mice, thus suggesting that the channel has no
tentious disagreements being focused on TRPA1. In heter- detectable inuence on cold sensitivity in nave animals (Chen
ologous expression systems, cold-evoked TRPA1 responses et al 2011). With some distance from this particular debate
were transient, which differed from the sustained responses and time for more detailed analysis, it is clear that TRPA1 is
to noxious cold observed in isolated sensory neurons (Thut gated by noxious cold (Karashima et al 2009). It is also clear
et al 2003), single-unit electrophysiology (Bessou and Perl that the channel contributes to injury-induced cold hypersen-
1969, Iggo 1969, Hensel and Iggo 1971), and psychophysi- sitivity (del Camino et al 2010). Finally, as yet unidentied
cal studies (Kenshalo and Scott 1966, Johnson et al 1973). mechanisms must contribute to the response to acute noxious
Data from some of the initial studies of cold transduction in cold stimuli.
isolated sensory neurons implicated the closing of K+ channels TRPM8. Data from a number of different lines of investi-
as a contributing (Viana et al 2002) if not primary mechanism gation support the notion that TRPM8 contributes to the
(Reid and Flonta 2001a). Others failed to detect a response response to innocuous cooling. This includes single-cell poly-
to noxious cold with TRPA1, even in comparable heterolo- merase chain reaction of isolated sensory neurons (Nealen
gous expression systems (Jordt et al 2004). Subsequent data et al 2003), single-unit electrophysiology, and behavioral data
with TRPA1 null mutant mice suggested that the contribu- from null mutant mice (Bautista et al 2007, Knowlton et al
tion of TRPA1 to the response to acute noxious cold stimuli 2011). The only point of contention over TRPM8 is whether
was minimal, if detectable at all (Bautista et al 2006, Kwan this channel also contributes to nociceptive behavior. In the
et al 2006). Data derived from TRPA1-selective antagonists absence of tissue injury, the answer to this question appears to

be no because the channel does not code well into the noxious TRPV2. The thermal threshold for TRPV2, as well as its pres-
range, it is present in a subpopulation of neurons that have ence in a subpopulation of DRG neurons with a medium-
properties of non-nociceptive afferents (Nealen et al 2003, diameter cell body, was an excellent t with the available
Bautista et al 2007), and there is little change in behavior single-unit and psychophysical data (Treede et al 1995). Pre-
in response to noxious cold stimuli in TRPM8 null mutant vious data from the primate had revealed two types of noci-
mice (Bautista et al 2007, Babes et al 2011). However, high- ceptive afferents with axons conducting in the A range. Type
dose menthol applied topically in humans is used to generate II AMHs (A bers responsive to mechanical and heat stimuli)
hyperalgesia. Moreover, in the presence of tissue injury, cold a higher threshold for activation than did heat-responsive C
hypersensitivity is attenuated in TRPM8 null mutant mice bers but a very short utilization time (i.e., were activated
(Xing et al 2007) and with a TRPM8 antagonist (Knowlton very rapidly). These bers were thought to be primarily
et al 2011). Nonetheless, several additional lines of evidence responsible for the behavioral responses to acute noxious
argue against a role for TRPM8 in the cold sensitivity asso- stimuli. Data from rodents indicated that there was a rough
ciated with nerve injury (Katsura et al 2006, Caspani et al correlation between cell body diameter and axon conduction
2009). Whether the putative role for TRPM8 in nociception velocity and suggested that neurons giving rise to axons con-
is due to de novo expression of TRPM8 in nociceptive affer- ducting in the A range should be medium diameter (Lawson
ents (Djouhri et al 2004; but see Caspani et al 2009) and/ 2002). Thus, TRPV2 had the right biophysical properties and
or changes in the central nervous system such that input via was in the right population of afferents. Closer inspection of
cool-responsive neurons is able to engage a nociceptive circuit these correlational studies, however, reveals that there is no
remains to be determined. correlation between cell body size and axon conduction veloc-
TRPV3 and TRPV4. Unfortunately, because warm bers ity for neurons with a medium-diameter cell body (Lawson
are generally absent in rodents, progress in our understand- 2002). More problematic is that TRPV2 null mutant mice
ing of the relative contribution of TRPV3 and TRPV4 to the appear to have no decits in heat sensitivity, even with very
response to warmth has been slow. Whether these channels intense stimuli (Park et al 2010). Therefore, if there is another
contribute to the response to innocuous warming in other heat transducer in this population of afferents, it has yet to be
species remains to be determined. However, results from null identied.
mutant mice and the use of non-selective TRP channel block-
ers (St Pierre et al 2009) indicate that these channels have little Other Thermotransducers
role in the afferent or behavioral response to innocuous warm K2P Channels. Consistent with the evidence described above
or noxious heat. Because rodents appear to have the ability to that there must be other thermotransducers contributing to
discriminate temperatures in the innocuous warm range, these temperature sensation, at least four other channels have been
observations suggest that other channels must contribute to identied that are gated by temperature. The rst of these were
warmth transduction. the K2P channels TREK-1 and -2 and TRAAK (Noel et al
TRPV1. There has also been little dispute over whether 2009). These channels are activated by increases in tempera-
TRPV1 is activated by noxious heat. The response to heating ture over a range from approximately 28 to 42C. Because
in some isolated sensory neurons is blocked by TRPV1 antag- they are active at rest, the converse is also true, with channel
onists and absent in TRPV1 null mutant mice (Caterina et al activity being decreased over the same range. TASK has com-
2000). The single-unit response to noxious heat ramps may parable temperature sensitivity but far less dramatic changes
be attenuated but is not lost in null mutant mice (Caterina in activity associated with warming (Noel et al 2009). There
et al 2000), and the behavioral response to noxious heat is is also evidence that a 4-aminopyridinesensitive K+ chan-
also not lost with TRPV1 antagonists (Wong and Gavva nel contributes to cold transduction (Viana et al 2002), but
2009) and in null mutant mice (Caterina et al 2000). The this channel has yet to be identied. As noted above, all four
most pronounced phenotype, at least with respect to ther- thermosensitive K2P channels are present in sensory neurons.
mosensation, in null mutant mice is the absence of inam- The involvement of a leak K+ conductance in mediating the
matory heat hyperalgesia (Caterina et al 2000). Together, response to cooling is consistent with the underlying mecha-
these observations have several important implications. The nism predicted in one of the rst characterizations of cooling-
complete loss of a heat response in isolated sensory neurons evoked responses in isolated sensory neurons (Reid et al
from TRPV1 null mutant mice in the face of heat sensitivity 1999). Although the increase in K2P channel activity asso-
that persists in vivo suggests that (1) there are other thermo- ciated with warming should result in a decrease in afferent
transducers and (2) TRPV1 may not be present in primary activity potentially, thereby explaining the therapeutic value
afferents that contribute to thermosensation. The possibility of heat for the treatment of inammatory pain, one would
that these other transducers act in concert with TRPV1 to predict that these channels do not contribute the warming-
generate a normal response to heat is suggested by the induced increase in activity in warm bers. Consistent with
decrease in the slope of the single-unit stimulusresponse this prediction, double-null mutant mice decient in TRAAK
function (Caterina et al 2000). Subsequent data indicat- and TREK-1 have an increased response to heating and an
ing the presence of a subpopulation of afferents decient in inammatory heat hyperalgesia that is fully intact (Noel et al
TRPV1 immunoreactivity that were responsive to noxious 2009). The cooling phenotype in these mice is a little harder
heating and still present in TPRV1 null mutant mice con- to interpret because the animals show an increase in cold
rmed that there were additional heat transducers (Wood- sensitivity following injury. This is in contrast to the pre-
bury et al 2004). Finally, the prominent role of TRPV1 in diction that the loss of a channel that normally closes as a
inammatory heat hyperalgesia supported the conclusion means to enable a response to cooling should be associated
that activity in specic subpopulations of afferents mediates with an increase in the response to cooling in the absence of
specic types of pain. injury.
42 Section One | Neurobiology of Pain

TRPM3 inactivation but recovery from inactivation that is excep-

Recent evidence indicates that TRPM3 is also a heat-sen- tionally fast (Elliott and Elliott 1993, Flake et al 2004), a
sitive channel (Vriens et al 2011). It has a threshold for high threshold for activation, and a voltage dependence of
activation of about 30C, which can be sensitized by the inactivation curve that is relatively depolarized (Akopian
co-application of pregnenolone sulfate. Like TRPA1 and et al 1996). These properties alone can account for many
V1, the thermal sensitivity of TRPM3 appears to reect a of the unique properties of nociceptive afferents, such as
temperature-dependent shift in the voltage dependence of a high threshold for activation and the ability to continue
channel gating. Interestingly, in contrast to TRPM2, 4, and to re action potentials in the presence of sustained mem-
5, which also have thermal sensitivity in a temperature range brane depolarization (Gold 2000b). An additional feature of
comparable to TRPM3, TRPM3 null mutant mice exhibit Nav1.8 is that the channel is not inactivated by noxious cold
a decit in noxious heat sensitivity (Vriens et al 2011). temperatures (Zimmermann et al 2007). This is in contrast
Although the majority of TRPM3-expressing neurons also to other voltage-gated Na+ channels responsible for action
express TRPV1, the observation that TRPM3 is present in a potential initiation in low-threshold afferents. This difference
subpopulation of TRPV1-negative neurons suggests that this accounts for why cold tissue feels both numb and on re
transducer may contribute to the heat sensitivity observed in at the same time.
afferents from TRPV1 null mutant mice. Nevertheless, the
observation that heat sensitivity is still detectable in neurons
from TRPM3 null mutant mice in the presence of TRPV1
blockers suggests that at least one more heat transducer has Despite the fact that mechanosensation is the dominant
yet to be identied. modality of somatosensation and that mechanical hypersen-
sitivity is far more common than thermal or even chemical
TRPC5 hypersensitivity (e.g., see Backonja and Stacey 2004), mecha-
TRPC5 is the most recent addition to the thermosensitive notransduction remains the most poorly understood of the
family of ion channels (Zimmermann et al 2011). It is pro- stimulus modalities that activate the somatosensory system.
posed to function as a cool receptor with channel activity that This lack of understanding is not due to a dearth of puta-
is steeply temperature sensitive between 37 and 25C, where tive mechanotransducers since a number of ion channels
interestingly, only the homomeric channel is cold sensitive have been shown to be gated by mechanical stimuli. Rather,
whereas the TRPC5/TRPC1 heteromeric channel is not. The the problem appears to be due to the fact that data from
channel is detectable in approximately 32% of DRG neu- parallel lines of evidence are not internally consistent. Not
rons in a proportion that mirrors the size distribution of the only are there differences between the results obtained with
entire population of DRG neurons. The protein appears to isolated neurons, isolated organ preparation, and behavioral
be targeted to peripheral terminals, many of which termi- assays, but there are also differences between behavioral
nate in the supercial layers of the skin. The channel does assays engaging different body regions. Nevertheless, at least
not contribute to cold-evoked currents in isolated sensory two conclusions can be drawn from this data set at present.
neurons from TRPC5 null mutant mice, possibly because First, the process of mechanotransduction appears to involve
of preferential targeting in the periphery (Zimmermann several different mechanotransducers, and second, the under-
et al 2011). There are several compensatory changes in the lying mechanisms are likely to vary as a function of both
afferent properties of the TRPC5 null mutant, which was the type of stimulus (stretch versus pressure) and the tissue
used to explain the paradoxical increase in cooling-evoked stimulated.
activity in mechanosensitive C bers. Thus, absence of the
expected cooling phenotype in these animals (i.e., the loss ASIC Channels
of a cooling response) may be due to compensatory changes. Although ASICs have yet to demonstrate intrinsic mechano-
Alternatively, it was suggested that TRPC5 could play a sensitivity when expressed in heterologous expression sys-
role in responses to cooling that are not tied to behavior tems, several lines of evidence suggest that these channels
(i.e., regulation of peripheral blood ow). Additional data may play a role in mechanotransduction. First, the channels
will be needed to further dene the role of this putative cold are members of a larger family of ion channels, degenerins,
transducer. identied in Caenorhabditis elegans in genetic screens for
mechanosensory defects (Goodman et al 2002, OHagan et al
Nav1.8 2005). The closest mammalian homologue, ENaCs, have been
In contrast to other transduction modalities, transduction of shown to possess intrinsic mechanosensitivity in lipid bilay-
noxious cold stimuli is entirely dependent on the biophysi- ers (Ismailov et al 1997) and in heterologous expression sys-
cal properties of the voltage-gated Na+ channels that under- tems (Kizer et al 1997). Second, like degenerins, ASICs are
lie action potential initiation (Zimmermann et al 2007). As also sensitive to amiloride and related compounds (Kizer et al
already touched on above, the ultimate fate of a generator 1997). Third, the channels are present in peripheral terminals
potential depends on a number of factors, not the least of (Price et al 2000, 2001; Garcia-Anoveros et al 2001). Unfor-
which are the density, relative distribution, and biophysical tunately, there is considerably more conicting evidence or
properties of the voltage-gated Na+ channels that ultimately evidence against a role for ASICs in mechanotransduction
transform the passive depolarization initiated by the trans- than for it. Mechanically evoked currents in isolated sensory
ducer into an action potential. In nociceptive afferents, the neurons from ASIC2/3 double-null mutant mice are fully
voltage-gated Na+ channel Nav1.8 plays a particularly impor- intact (Drew et al 2004). The mechanical stimulusresponse
tant role in this process. This channel has a number of unique properties of afferents from ASIC1 null mutant mice were
features, including relatively slow kinetics of activation and comparable to those in wild-type mice when studied in a skin

nerve preparation (Page et al 2004). A reduction in the slope expression cloning approach in a heterologous expression
of the stimulusresponse function with no change in threshold system in which hits were identied by the cells response
was observed in one study of rapidly adapting low-threshold to a poke with a small pipette (Fig. 2-5). Both channels
mechanosensitive afferents from an ASIC2 null mutant (Price are widely expressed across phyla, as well as in a number
et al 2000); however, comparable changes were not observed of tissues in rodents. Piezo2 appears to play a particularly
in a subsequent study (Roza et al 2004). Even more confus- important role in the rapidly activating and rapidly inactivat-
ing was the observation that in ASIC3 null mutant mice there ing poke-evoked currents in isolated sensory neurons. The
was a decrease in the mechanosensitivity of A mechano- contribution of these channels to mechanosensation in vivo
sensitive afferents but an increase in the mechanosensitivity has yet to be determined, but Piezo does appear to be a bona
of low-threshold, rapidly adapting afferents. An increase in de mechanotransducer. That is, when expressed it is suf-
inammatory mechanical hypersensitivity was also observed cient to carry an inward current when the cell is mechani-
in these mice (Price et al 2001). In contrast to the role of cally stimulated. There are probably many ancillary proteins
ASICs in the skin, ASIC1, 2, and 3 appear to contribute to that modulate the mechanically induced currents, several dis-
the mechanosensitivity of visceral afferents. ASIC1 appears to cussed here, but this is not a sufcient basis to consider them
inhibit mechanosensitivity such that afferents of the GI tract mechanotransducers.
are even more excitable in ASIC1 null mutant mice (Page et al
2004, 2005). The response properties of some subpopulations TRPA1
of GI afferents were increased whereas others were decreased TRP Channels
in ASIC2 null mutant mice (Page et al 2005). Most striking, One of the most controversial putative mechanotransducers
however, was the suppression of mechanosensitivity observed is TRPA1. The rst suggestion that the channel might func-
in all but one subpopulation of GI afferents dened by the tion as a mechanotransducer came from observations that the
response properties to various mechanical stimuli (Jones et al channel is present in hair cells, where it is localized in the
2005, Page et al 2005). hair tips, and that protein knockdown results in the inhibition
of receptor cell function (Corey et al 2004). Subsequent data
Piezo1 and 2 from TRPA1 null mutant mice ruled out a role for TRPA1
The most recent additions to the list of channels with as the mechanotransducer in cochlea hair cells (Kwan et al
intrinsic mechanosensitivity are Piezo1 and 2 (Coste et al 2006). In isolated cells, there is evidence both for and against
2010). These channels were identied through a heroic a role for TRPA1 in mechanically activated (MA) currents. In

5 m 200

100 pA 100

50 msec
100 msec (mV)
80 40 40 80

100 pA (pA)

HC-030031 (10 M)
2 min

100 pA
100 msec

Figure 2-5. Piezo2 underlies rapidly activating and rapidly inactivating mechanically activated (MA) currents in Neuro2A (N2A) cells and sensory
neurons. A, Representative traces of MA inward currents expressed in N2A cells. Cells were subjected to a series of mechanical steps consisting of 1-m move-
ments with a stimulation pipette (inset drawing, arrow) in the whole-cell patch conguration at a holding potential of 80 mV. B, Average currentvoltage
relationships of MA currents in N2A (n = 11) cells. The inset shows representative MA currents evoked at holding potentials ranging from 80 to +40 mV
(applied 0.7 second before the mechanical step). A comparable current is detectable in sensory neurons that is selectively reduced with small interfering RNA
against Piezo2. Sustained MA currents are also detected in sensory neurons (C). However, the sustained current is completely blocked by the TRPA1-selective
antagonist HC-030031. Results from these studies indicate that there are several mechanotransducers in sensory neurons. (A and B, From Coste B, Mathur J,
Schmidt M, et al 2010 Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science 330:5560; C, from Vilceanu
D, Stucky CL 2010 TRPA1 mediates mechanical currents in the plasma membrane of mouse sensory neurons. PLoS One 5:e12177.)
44 Section One | Neurobiology of Pain

ND-C cells, a cell line derived from neonatal rat DRGs, MA were used (Cattaruzza et al 2010). In a second study, the
currents are cationic, rapidly activating, and slowly inactivat- response to distention was attenuated in the null mutant.
ing. TRPA1 is not present in these cells normally, thus sug- The response to distention was also attenuated following
gesting that other channels underlie the MA evoked currents antisense knockdown of TRPA1 (Kondo et al 2009). Unfor-
(Rugiero and Wood 2009). Furthermore, transfecting ND-2 tunately, interpretation of the behavioral data has been com-
cells with TRPA1 failed to alter the MA currents in these cells. plicated by evidence that TRPA1 acts at the central terminal
In contrast, slowly inactivating MA currents are completely of nociceptive afferents, where it facilitates nociceptive signal-
absent in neurons from TRPA1 null mutant mice and com- ing. Consequently, spinal block of TRPA1 is antinociceptive
pletely blocked with the TRPA1 antagonist HC-030031 (Vil- (McGaraughty et al 2010, Wei et al 2010). Although TRPA1
ceanu and Stucky 2010) (see Fig. 2-5). Interestingly and at remains a target of active investigation, if conclusions can be
least partially consistent with results obtained in ND-C cells, drawn from the data available on TRPA1 and its potential
heterologous expression of TRPA1 in HEK293 cells failed to role as a mechanotransducer, they are the following: First, the
alter the MA currents in these cells, which led the authors to role of TRPA1 in mechanotransduction is limited to modula-
suggest that TRPA1 alone was not sufcient to mediate MA tion of evoked activity. This implies that other channels or
evoked currents. transducers play a dominant role in the process. Second, con-
In isolated skin nerve preparations from TRPA1 null sistent with this modulatory role, TRPA1 plays a signicant
mutant mice, the entire mechanical stimulusresponse func- role in the injury-induced increase in mechanosensitivity, as
tion in C bers and only the top of the stimulusresponse has been demonstrated in models of both somatic and visceral
function in A bers were suppressed (Kwan et al 2009), with inammation, as well as in several models of peripheral nerve
no change in threshold in either population. Surprisingly, the injury (Petrus et al 2007, Eid et al 2008, Wei et al 2009, da
stimulusresponse function for slowly adapting A bers is Costa et al 2010, McGaraughty et al 2010).
also suppressed in TRPA1 null mutant mice, whereas that
for rapidly adapting A bers and D hairs is increased. Evi- TRPV4
dence of TRPA1 in keratinocytes was offered as one potential TRPV4 was known to function as an osmolality-gated ion
explanation for the widespread impact of the loss of TRPA1. channel (Strotmann et al 2000) before the realization that the
However, in contrast to the original descriptions of TRPA1 in channel also functions as a thermoreceptor. The channel is
which it was indicated that channel expression was restricted activated by hypertonic solutions, presumably because of the
to a subpopulation of small-diameter TRPV1-expressing sen- mechanical stress associated with cell shrinkage. The channel
sory neurons (Story et al 2003), evidence of TRPA1 expres- is widely distributed in a number of different cell types, includ-
sion was detected in all sizes of DRG neurons, as well as in the ing primary afferents, probably reecting the fact that the abil-
terminals of low-threshold afferents. These results suggested ity to respond to changes in tonicity is essential to most cell
that changes in ring properties were due to the actions, or types, particularly epithelial cells. However, in sensory neu-
lack thereof, of TRPA1 in all populations of sensory neurons. rons the channel is essential for the pain behavioral response
The subsequent observation that a TRPA1 antagonist pro- associated with hypertonic solutions (Alessandri-Haber et al
duced a suppression of activity in C bers conrmed a role 2005). Interestingly, although TRPV4 is responsive to swell-
for TRPA1 in the response to mechanical stimulation in these ing, chemical, and thermal stimuli, each modality activates
neurons (Kerstein et al 2009). However, failure of the TRPA1 the channel via distinct pathways (Vriens et al 2004). Like
antagonist to inuence the mechanical response properties of other TRP channels, TRPV4 may play a more important role
A bers or the response of widedynamic range neurons to in mechanosensation in the presence of injury, as suggested by
low-intensity mechanical stimuli (McGaraughty et al 2010) the observation that mechanical hypersensitivity is attenuated
raises the possibility that at least some of the results obtained in TRPV4 null mutant mice (Alessandri-Haber et al 2004,
with the null mutant mouse are due to compensatory changes Chen et al 2007, Cenac et al 2008, Zhang et al 2008).
rather than the loss of TRPA1 itself. Of note, the observa-
tion that TRPA1 expression in primary afferents may be more K2P
generalized than originally thought has yet to be repeated. There are at least three K2P channels present in sensory neu-
Interestingly, TRPA1 appears to contribute to the response rons that have been shown to have mechanosensitivity: TREK-
of all types of visceral afferents, including vagal afferents, to 1, TREK-2, and TRAAK (Maingret et al 1999a, 1999b; Bang
punctate mechanical stimuli but not to stretch (Brierley et al et al 2000). TREK-1 was rst described as a chemotransducer
2009), again highlighting the importance of both the type and activated by arachidonic acid (Fink et al 1998) and inhibited
site of stimulation on the relative contribution of a putative by cAMP (Fink et al 1996). It was subsequently shown to be
transducer. activated by osmotic swelling, stretch, and membrane crena-
The behavioral data are consistent with a role for TRPA1 tors (Maingret et al 1999b). TREK-2 and TRAAK have the
in the response to noxious mechanical stimuli. The response same mechanosensitive properties as TREK-1. Despite evi-
to punctate mechanical stimuli (i.e., the von Frey test) is dence that the channels are differentially regulated in the pres-
attenuated in TRPA1 null mutant mice, as is the response to ence of tissue injury in a manner consistent with a role in the
noxious paw pressure in rats following administration of the injury-induced hypersensitivity model (Marsh et al 2012), the
TRPA1 antagonist HC-030031 (Wei et al 2009). However, relative contribution of K2P channels to mechanosensitivity
one would have predicted that the response to colonic dis- remains to be determined.
tention would be unaffected by the loss of TRPA1 given the
selective decit in the response to punctate mechanical stimuli T-Type Ca2+ Channel (Cav3.2)
in TRPA1 null mutants. Nevertheless, this was observed in Transient or T-type Ca2+ channels are members of the volt-
only one of two studies in which TPRA1 null mutant mice age-activated Ca2+ channel family that have a low threshold

for activation (Catterall et al 2005). They are therefore also are probably the best characterized in this regard. A wide vari-
referred to as low-threshold voltage-activated channels. The ety of chemo-, thermo-, and mechanotransducers are report-
subunit of these channels is a large molecule with four edly present on these cells, including nAChRs, bradykinin
homologous domains, each of which has six transmembrane receptors (B1 and B2), and TRP channels (TRPA1, TRPM8,
segments with a pore loop between segments 5 and 6 and and TRPV12, 4) (see Birder 2011 for review). The only
a voltage sensor in segment 4. Thus, the subunit has all transducer present in urothelial cells minimally represented
the components necessary for a functional channel. Three in sensory neurons (Hermanstyne et al 2008) is the ENaC,
subunits for the low-threshold channel have been identied which is related to ASIC channels (see above). Urothelial cells
and designated Cav3.13.3. Of these, Cav3.2 is enriched in are activated by thermal, mechanical, and chemical stimuli,
a subpopulation of sensory neurons that appear to innervate and they release a variety of mediators that are able to acti-
D hairs (Shin et al 2003). More importantly, the response to vate and/or sensitize afferents. These mediators include ACh,
mechanical stimulation of the receptive eld of D-hair units is ATP, reactive oxygen species (nitric oxide), peptides, neuro-
selectively attenuated with the T-type channel blocker mibe- trophins, cyclooxygenase metabolites, and cytokines (Birder
fradil. There is evidence that T-type currents are also enriched 2011). Of these, ATP has received the most attention because
in a subpopulation of nociceptive afferents and that sensitiza- it was the rst mediator shown to be released in response to
tion of these channels results in a decrease in the mechanical bladder stretch. This observation provided a mechanism for
threshold (Todorovic and Jevtovic-Todorovic 2006). How- mechanical transduction via ATP binding P2X receptors on
ever, data from a Cav3.2 null mutant mouse suggest that the primary afferents that terminate in close contact to urothe-
mechanical response properties of nociceptive afferents are lial cells. Consistent with this model, there is an increase in
minimally altered, thus indicating a minor role for this chan- release of ATP from the urothelium of both animals (Birder
nel in these afferents. This is in contrast to the response of et al 2003) and humans (Sun and Chai 2002) with intersti-
D-hair bers in this knockout line, which is reduced by more tial cystitis, a painful inammation of the bladder. TRPV1
than 50%, largely as a result of an increase in the mechani- is another channel that has received a lot of attention both
cal threshold and utilization time (Shin et al 2003). Although because it appears to contribute to normal bladder function
data in support of a role for T-type channels in the mechani- (i.e., bladder afferents from TRPV1 null mutant mice have
cal response properties of D hairs are compelling, the channel a lower response to bladder distention) (Birder et al 2002)
has received the most attention for its role in mediating the and because TRPV1 agonists can be used to produce affer-
hypersensitivity observed in response to a number of pain- ent desensitization and provide some relief for patients with
producing manipulations, including hydrogen sulde injec- pain associated with bladder hypersensitivity disorders (Cruz
tion, diabetic and post-traumatic neuropathy (including a 1998).
compressed DRG model; Wen et al 2006), and a model of The bladder urothelium is proving to be far from unique
irritable bowel syndrome (Marger et al 2011). Consistent with respect to its potential role in sensory transduction inas-
with these observations is that a number of small-molecule much as similar roles have been implicated for epithelial cells
inhibitors of T-type channels have antinociceptive efcacy in lining the GI tract (Wynn et al 2004) and airway (Button
a variety of animal models of persistent pain (Zamponi et al et al 2007). Epithelial cell signaling appears to be even more
2009). complex in the skin, where keratinocytes have been shown to
express not only a wide variety of transducers but also chan-
nels that could serve to facilitate signaling, such as voltage-
gated Na+ channels (Zhao et al 2008, Dussor et al 2009, Hou
It is clear from the preceding discussion that in primary affer- et al 2011). Like the bladder, there is considerable hetero-
ents, transducer specicity is rare. Many transducers are geneity among keratinocytes with regard to the expression
activated by several stimulus modalities. Even though the of various transducers and ion channels. Consistent with the
functional implications of this polymodality are still being fact that skin consists of stratied epithelium, there is also
worked out, the chemosensitivity of many of the thermo- and heterogeneity in the distribution of channels between layers.
mechanotransducers makes interpretation of results from Interestingly, this pattern appears to be disrupted in the pres-
intact preparations difcult, at least with respect to the con- ence of tissue injury and under pathological conditions (Zhao
tribution of a specic transducer to the response to a specic et al 2008), thus raising the possibility that these changes
stimulus. For example, it will be difcult to distinguish the contribute to the associated alterations in sensation. Much
relative contribution of the mechanosensitive properties of remains to be determined, however, with respect to the role
the transducer from its chemosensitive properties if it is pos- of these cells in signal transduction, not the least of which is
sible that chemicals that activate the transducer are released the answer to how modality specicity is achieved in the ner-
from other cells in response to mechanical stimuli. Evidence vous system if all modalities of stimuli result in the release of
abounds that chemicals are released from thermally (Patward- common mediators such as ATP.
han et al 2010) and mechanically (Burnstock 2009) stimu-
lated tissue, thus making this a serious technical hurdle. LESSONS LEARNED FROM
Our understanding of the molecular mechanisms of transduc-
The focus up until now has been on transduction in sensory tion is complicated by the apparent paradox between nave
neurons. However, it is becoming increasingly clear that many and injured tissue with regard to the relative contribution of
putative transducers are not only present but also functional putative transducers to sensation since the contribution often
in other cell types. The bladder epithelium, or urothelial cells, appears to be greater in the presence of tissue injury. This may
46 Section One | Neurobiology of Pain

be due to the fact that in some tissues (e.g., skin), the relative inuence on the output of the neuron. For example, very slow
contribution of C-ber activity is minimal under normal con- depolarization in a neuron in which initiation of an action
ditions and becomes apparent only in the presence of injury- potential is dependent on a voltage-gated Na+ channel subject
induced hypersensitivity (Khasar and Levine 1996). This to steady-state inactivation may drive the inactivation of Na+
differential contribution of ber types may also explain why channels before initiation of the action potential. Similarly, a
putative transducers appear to contribute more signicantly large and rapid depolarization associated with activation of
to the response of nave visceral tissue, given the relative TRPV1 may drive the membrane potential to 0 mV, the rever-
dearth of myelinated bers that innervate visceral structures. sal potential for TRPV1, and enable the generation of few if
Of course, the implication of such a suggestion is that we have any action potentials before a depolarization-induced inacti-
yet to identify transducers underlying the response of the more vation of voltage-gated Na+ channels. Another critical point
rapidly conducting A and A bers thought to dominate the of interaction between the transducer and ion channels under-
response to acute noxious stimulation of nave cutaneous tis- lying the active electrophysiological properties is at the level
sue. The paradox may also reect the fact that many of the of the permeant ions. That is, TRPV1 is highly permeable to
known transducers are dramatically up-regulated in the pres- Ca2+, whereas ASIC3 is far more selective for Na+. The pres-
ence of tissue injury. Injury-induced changes in TRPV1 are an ence of a high density of Ca2+-dependent ion channels that
excellent example of transducer up-regulation. The channel is contribute to determination of the action potential thresh-
sensitized via an array of second-messenger pathways, includ- old and/or burst duration should respond very differently
ing those involving protein kinase A (PKA), protein kinase to stimuli engaging TRPV1 than to those engaging ASIC3.
C (PKC), phosphatidylinositol-3-kinase (PI3K), calcium- Conversely, Ca2+ inux via voltage-gated Ca2+ channels is not
calmodulindependent kinase II protein (CaMKII), and p38/ only important for peripheral transmitter release and there-
mitogen-activated protein kinase (MAPK), which results in an fore the efferent function of afferents but can also facilitate
increase in channel activity, a decrease in desensitization, and/ the desensitization of channels such as TRPV1 (Vyklicky et al
or an increase in receptor density as a result of translocation 2008).
to the membrane (Gold and Gebhart 2010). On a slower time The literature is now full of descriptions of injury-induced
scale, there is evidence that TRPV1 protein is increased via changes in an array of ion channels that underlie active elec-
post-transcriptional mechanisms (Ji et al 2002) and that the trophysiological properties. This includes changes in a variety
distribution of the channel is increased in DRG neurons, thus of voltage-gated K+ channels, Na+ channels, Ca2+ channels,
suggesting alterations in transcriptional machinery as well and Ca2+-dependent K+ and Cl channels in a manner con-
(Breese et al 2005). Following nerve injury there is evidence sistent with an increase in afferent excitability (Harriott and
that the channel is even expressed in A bers (Rashid et al Gold 2009a). Changes in all channel types are associated
2003). These observations highlight the importance of both with both the acute actions of inammatory mediators and
the time course of changes after injury and injury-induced longer-term changes in channel distribution and gene expres-
changes in the relative contribution of afferent subpopula- sion. Importantly, as noted above, the nature and timing of
tions to pain after injury. the changes depend on a number of factors, including the type
Changes in the properties of ion channels regulating the of injury, the site of injury, the previous history of the injured
passive and active electrophysiological properties of the affer- tissue, age, and sex.
ent are also likely to contribute to the increase in the relative Finally, data from nerve injury models have highlighted
impact of putative transducers on the generation of afferent the importance of transducer distribution on the emergence
activity in the presence of tissue injury. That is, the fate of the of ectopic activity. There is evidence that transducers may
generator potential depends on both the passive and active be inserted into the axon membrane following nerve injury
electrophysiological properties of the afferent terminal, with and thereby result in the emergence of mechanical, thermal,
passive properties that include resting membrane potential and presumably chemical sensitivity at sites along the axon
and input resistance inuencing the magnitude of the gen- (Michaelis et al 2000, Grossmann et al 2009, Janig et al
erator potential and the distance over which it is passively 2009). This process appears to occur much more readily in
spread. The resting membrane potential will also inuence muscle afferents. The process is also likely to occur within
the availability of many of the ion channels underlying active ganglia and contribute to the emergence of ectopic activity
electrophysiological properties. Channels that contribute to arising from within the ganglia following traumatic nerve
passive properties in primary afferents include the P2K chan- injury (Devor 1999). The emergence of sources of activity at
nels, which are dynamically regulated by a variety of media- locations remote from the site of injury or even the painful tis-
tors (see above), as well as over the long term by changes in sue can add to the difculty in treating neuropathic pain with
expression (Marsh et al 2012). Voltage- and Ca2+-modulated peripherally targeted interventions.
ion channels underlie active electrophysiological properties,
and these will determine the action potential threshold, the CONCLUSION
amplitude and duration of the action potential, the ampli-
tude and duration of the afterpotential, and more stimulus The past 15 years have yielded an explosion of information
response properties such as the interspike interval and burst regarding the molecular mechanisms of sensory transduc-
duration (Harriott and Gold 2009a). tion. An array of putative transducers have been identied,
Because the generator potential provides the underlying as have details regarding mechanisms underlying their acti-
drive for activation of these other ion channels, the interaction vation. As is true of many aspect of science, the more we
between the amplitude and duration of the generator poten- learn about something, the more complicated it becomes.
tial with the biophysical properties of the channels underlying This has been particularly true of our understanding of ther-
the active electrophysiological properties can have a profound mal transduction, which seemed so clear 5 years ago but is

considerably less so now. This complexity has clearly proved the treatment of pain. Nevertheless, although it is clear that
to be a barrier to the development of novel therapeutic there is still much to learn about sensory transduction, novel
approaches for the treatment of pain. With multiple channels approaches are on the horizon that should provide relief for
working in parallel and/or differentially contributing to the many in need.
response in one ber type or after a particular type of injury,
it should not be surprising that an effective blocker of a par- The references for this chapter can be found at www
ticular channel has not emerged as the next silver bullet for .expertconsult.com.
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Chapter Inammatory Mediators
and Modulators of Pain
3 John M. Dawes, David A. Andersson, David L.H. Bennett,
Stuart Bevan, and Stephen B. McMahon

their roles have been redened in some cases. Prostaglan-

SUMMARY din E2 (PGE2), for instance, is now recognized as playing a
Disease and injury frequently result in pain and prominent role in central nervous system (CNS) as well as
hyperalgesia. These abnormal sensory events arise in peripheral tissues. The newly identied mediators include a
part from the action of inammatory mediators on variety of factors produced and released from non-neuronal
the peripheral terminals of nociceptive neurons. In cells, often immune and glial cells. There is now a rapidly
this chapter we begin by reviewing the different ways expanding evidence base that these are important mediators
in which such mediators bring about the activation of persistent pain states and can act at a number of loci.
or sensitization of nociceptive terminals. We then This chapter focuses on the cellular characteristics of noci-
consider the biological effects and potential impor- ceptive afferent neurons, their ion channels, and their sig-
tance of different inammatory mediators. The list of nal transduction pathways and discusses the ways in which
mediators has steadily been increasing and includes inammatory mediators impinge on these basic properties.
not only traditionally recognized molecules such as In particular, we rst review the cellular mechanisms of acti-
arachidonic acid metabolites and bradykinin but also vation and sensitization of nociceptors. Then we discuss the
other small molecules such as adenosine triphosphate roles and actions of particular immune cells and specic pain
and nitric oxide. Additionally, evidence has accumu- mediators, starting with a group of small molecules often rap-
lated for an important role of a series of inamma- idly released into damaged tissue. We conclude with a review
tory cytokines and chemokines, such as tumor necrosis of the actions of another group of peripheral pain media-
factor- and interleukin-1, and growth factors, par- tors and modulators: the pro-inammatory cytokines, some
ticularly nerve growth factor, which are all capable chemokines, and some neurotrophic factors, which in addi-
of changing the response properties of pain-signal- tion to their traditionally recognized roles, are all capable of
ing neurons. They achieve this in a variety of ways, changing the response properties of pain-signaling neurons.
including activation or sensitization of nociceptive The topic of neuro-immune interactions within the CNS is
terminals, as well as regulation of gene expression by considered in Chapter 4.
nociceptors. Immune cells are an important source of
inammatory mediators, cytokines, and some growth OVERVIEW OF INFLAMMATORY
factors. Recently, it has become clear that they modu- MEDIATOR ACTIONS
late pain processing not just by release of mediators
into peripherally damaged or diseased tissue but also A large number of endogenously generated factors produce
by release of the same mediators into the central ner- pain when injected into peripheral tissue. Many of these sub-
vous system. stances can also sensitize nociceptors. That is, they reduce
the threshold for activation of nociceptors by one or more
stimulus modalities and/or increase the responsiveness of
nociceptors to suprathreshold stimulation. This process of
sensitization is recognized as being of critical importance in
INTRODUCTION many chronic pain states; it is precisely this aberrant excit-
ability of nociceptors that causes a large part of the sensory
A long-standing interest for pain scientists has been the iden- abnormality. Some features of the sensitization process are
tication of chemical mediators released into injured or dis- described in Chapter 1. Here we rst review the cellular mech-
eased tissues that are responsible for the abnormal pain states anisms by which sensitization occurs.
associated with these disorders. For some time, attention
was focused on a small number of molecules such as pros-
Receptors and Effectors
taglandins and bradykinin. These factors were known to be
produced as a result of tissue damage or inammation and Sensory nerves express a variety of receptors for inamma-
were thought to be responsible for activation and sensitiza- tory mediators. Different classes of nociceptors express dis-
tion of peripheral pain-signaling sensory neurons; that is, they tinct patterns of receptors. The receptors fall into three main
were seen as the principal peripheral pain mediators. During classes: G proteincoupled receptors (GPCRs), ligand-gated
the past decade or so, evidence has emerged for many novel ion channels, and the cytokine receptors or receptor tyrosine
pain mediators. The old ones have not disappeared, although kinases (Fig. 3-1).


activated. Activation of Gs stimulates adenylate cyclase to

A raise the level of cyclic adenosine monophosphate (cAMP)
H+ ATP Heat/H+/capsaicin and activate protein kinase A (PKA) in the neuron, whereas
ASIC P2X3 TRPV1 Gi inhibits the activity of adenylate cyclase to lower cAMP
levels. Although many cAMP effects are mediated by PKA,
Mechanical other mechanisms may be operative. For example, cAMP
PGE2 EP Ligand-gated can activate Epac (exchange protein directly activated by
Bradykinin B2
Primary sensory cAMP), a guanine nucleotide exchange factor, which leads
G-protein neuron terminal to activation of the isoform of protein kinase C (PKC-).
Adrenaline 2 receptors
Stimulation of Gq/11 activates phospholipases, notably phos-
ATP P2Y Tyrosine kinase pholipase C (PLC), which generates inositol triphosphate
(IP3) and diacylglycerol (DAG) from the membrane lipid
NGF trkA
precursor phosphatidylinositol 4,5-bisphosphate (PIP2). Gq
activation can also stimulate PLA2, which cleaves membrane
phospholipids at the sn-2 position to produce the prosta-
glandin precursor arachidonic acid. G-protein control of
Ligand-gated Voltage-gated
channels channels cellular function can also involve direct action of sub-
units on ion channels and enzymes, such as PLC (see Smrcka
ASIC P2X3 TRPV1 Na+ Ca2+ K+ 2008, Zylbergold et al 2010).

Ion Channels
EP 1. [Ca2+] Some inammatory mediators act by directly gating the ion
G-protein B2 2. Adenylyl cyclase cAMP? PKA channels expressed by sensory neurons. Notable examples in
3. PLC DAG PKC this class are adenosine triphosphate (ATP; acting via P2X
receptors 2 IP3 [Ca2+]
channels), protons (acting via acid-sensing ion channels
P2Y 4. Ras MEK ERK 1.2 [ASICs] and transient receptor potential vanilloid 1 [TRPV1]),
and the lipid activators of TRPV1. All these ion channels are
trkA cation selective and are permeable to either sodium ions or
both monovalent and divalent cations. In all cases the ion
ow evoked by channel opening depolarizes the sensory neu-
rons and leads to neuronal ring.
Ligand-gated Voltage-gated Receptor Tyrosine Kinases
channels channels The third general type of receptor includes cytokine recep-
tors activated by mediators such as interleukin-1 (IL-1) or
ASIC P2X3 TRPV1 Na+ Ca2+ K+
tumor necrosis factor- (TNF-) and the receptor tyrosine
kinases for neurotrophic factors, such as the receptors for
p p
EP p nerve growth factor (NGF), brain-derived neurotrophic
Receptor sensitization factor (BDNF), glial cell linederived neurotrophic factor
G-protein B2
(GDNF), and artemin. Both classes of receptors have mono-
receptors 2 Channel sensitization
mers derived from a single transmembrane segment with a
P2Y Gene expression large extracellular ligand-binding domain. The cytosolic
domain of receptor tyrosine kinases contains an intrinsic
protein tyrosine kinase catalytic site, whereas the cytosolic
trkA domain of cytokine receptors is generally associated with a
separate protein kinase that is recruited to the complex either
Figure 3-1. Peripheral sensitization of nociceptive neurons. A, Some of
directly or via adapter proteins. The functional receptors are
the different stimuli (and the receptors that they act on) that can lead to acti- either dimers or trimers, which either exist normally or are
vation and sensitization of the peripheral terminals of nociceptive neurons. formed by cross-linking of adjacent monomers by the ligand.
B and C show the main effector mechanisms and second-messenger cascades In either case, ligand binding activates kinase pathways that
underlying sensitization, respectively. ASIC, acid-sensing ion channel; DAG, affect gene transcription and can also elicit acute effects on
diacylglycerol; ERK, extracellular signalregulated kinase; IP3, inositol tri-
phosphate; MEK, mitogen-activated protein/ERK kinase; NGF, nerve growth neuronal function.
factor; PGE2, prostaglandin E2; PKA, protein kinase A; PKC, protein kinase
C; PLC, phospholipase C; TRPV1, transient receptor potential vanilloid 1. Nitric Oxide and Cyclic Guanosine
Many changes are effected by phosphorylation of receptors or channels (P). Monophosphate
In addition to receptor-mediated signaling, cells also signal
via nitric oxide (NO). NO is an important intercellular media-
G ProteinCoupled Receptors tor and is produced by many cells that have close physical
Many mediators produced during inammation, such as association with neurons both in the periphery and within the
bradykinin, serotonin, prostaglandins, and chemokines, spinal cord. NO is formed from l-arginine following activa-
act via GPCRs. These receptors elicit a specic biochemi- tion of the enzyme nitric oxide synthase (NOS) by calcium
cal response that depends on the type of G protein that is and other co-factors, including calmodulin. Three forms of
50 Section One | Neurobiology of Pain

NOS have been identied: neuronal NOS (nNOS), induc- for nociception in neurons that do not normally express the
ible NOS (iNOS), and endothelial NOS (eNOS), each with protein (Hudson et al 2001, Vellani et al 2004).
a distinct physiological role. nNOS and eNOS are both Ca2+/
calmodulin dependent and are present in both the spinal
cord and brain, whereas iNOS is functionally Ca2+ indepen- SPECIFIC PAIN MEDIATORS
dent and normally expressed in macrophages, inammatory Bradykinin
cells, and glia (for review see Benarroch 2011). NO diffuses
to its site of action, where it stimulates guanylate cyclase to There is a considerable body of evidence that kinins contrib-
produce cyclic guanosine monophosphate (cGMP). In turn, ute to the pathophysiological processes accompanying both
cGMP modies intracellular processes, including activation acute and chronic inammation. Bradykinin and the related
of protein kinases, ion channels, and phosphodiesterases. NO peptide kallidin (Lys0-bradykinin) are formed from kinino-
can also act in other ways, for example, by activating cyclo- gen precursor proteins following the activation of plasma or
oxygenase (COX) enzymes and by S-nitrosylation of proteins tissue kallikrein enzymes during inammation, tissue dam-
(Tegeder et al 2011). age, or anoxia. The activity of these kinins is terminated by
several degradative enzymes. Kininase I liberates the biologi-
cally active metabolites des-Arg9-bradykinin and des-Arg10-
Intracellular Signaling Pathways
kallidin, whereas kininase II and endopeptidases form inactive
Sensory nerves are activated and sensitized by inammatory metabolites (Calixto et al 2000, Marceau and Regoli 2004).
mediators in several ways (see Fig. 3-1B). Some mediators The biologically active kinins activate two distinct types of
directly activate cation channels and thus depolarize neu- G proteinlinked receptors. Bradykinin and kallidin act pref-
rons toward the voltage for initiation of an action potential. erentially at the B2 receptor, whereas des-Arg9-bradykinin
Other receptors activate intracellular pathways and inuence and des-Arg10-kallidin act with much higher afnity at the B1
neuronal sensitivity and excitability indirectly. These mecha- receptor than at the B2 receptor.
nisms include GPCR-mediated production of the second- B2 receptors are expressed constitutively on a wide range of
messenger molecules NO, COX, and lipoxygenase products cell types, including nociceptive sensory nerves, and admin-
of arachidonic acid. Phosphorylation or dephosphorylation istration of bradykinin evokes pain and sensitizes polymo-
of membrane proteins often regulates the transduction and dal nociceptors (see Mizumura et al 2009). Bradykinin acts
transmission of sensory signals (Fig. 3-1C), and this can occur directly on sensory nerves and can also act indirectly by
via PKA-, PKC-, mitogen-activated protein kinase (MAPK)-, evoking the release of other inammatory mediators from
or phosphatidylinositol-3-kinase/Akt-mediated phosphoryla- non-neuronal cells. There is good pharmacological evidence
tion or by dephosphorylation via protein phosphatases such that the acute and some of the long-term effects of bradyki-
as calcineurin. In addition to phosphorylation, some of the nin are mediated via the B2 receptor. For example, peptide
mediators that act on nociceptors can stimulate biochemical and non-peptide B2 receptor antagonists have analgesic and
processes such as methylation and lipid modication of pro- anti-hyperalgesic actions in animal models of inammatory
teins, and these pathways may be important in nociceptive pain (Dray and Perkins 1993; Perkins and Kelly 1993, 1994;
neurons. Asano et al 1997; Burgess et al 2000; Cuhna et al 2007; Val-
In general, the effect of sensitization is to increase the prob- enti et al 2010), as well as in some neuropathic pain models
ability that a given stimulus (ligand or voltage) will activate (Werner et al 2007, Luiz et al 2010). Interestingly, thermal
the target receptor or ion channel or increase the probabil- hypersensitivity is still evoked by complete Freunds adjuvant
ity that the neuron will be excited. Protein phosphorylation (CFA)-induced inammation in mice lacking the B2 receptor
is a well-known mechanism for controlling the activity of (Boyce et al 1996, Rupniak et al 1997, Ferreira et al 2001),
ion channels. For example, activity of the heat-sensitive ion but carrageenan-evoked thermal hypersensitivity is reduced
channel TRPV1 is modied by both PKC- and PKA-medi- (Boyce et al 1996, Rupniak et al 1997).
ated phosphorylation (Bhave et al 2003, Mohaptra and Nau In contrast to B2 receptors, B1 receptors are not normally
2005), and the level of membrane expression is regulated by expressed at signicant levels in normal tissue, except in some
src-mediated phosphorylation (Zhang et al 2005b). Control vascular beds, but their expression is induced by tissue injury
of transduction channel activity can also be regulated by and infection. This up-regulation of B1 receptors requires de
hydrolysis of PIP2 and removal of the tonic inhibition caused novo protein synthesis (Regoli et al 1978, Bouthillier et al 1987,
by PIP2 binding to the ion channel (see, e.g., Dai et al 2007). DeBlois et al 1991), and there is evidence that the induction is
Ion channels that control the excitability and ring frequency stimulated by the release of cytokines such as IL-1 and TNF-
of sensory neurons are also substrates for regulation by PIP2 from immunocompetent cells in the damaged tissue (Calixto
(Suh and Hille 2008) and phosphorylation (Gold 1999, Baker et al 2004, Cuhna et al 2007). Some effects of B1 agonists are
2005, Beyak and Vanner 2005, Stamboulian et al 2010, mediated via non-neuronal cells, where activation of the B1
Emery et al 2011). receptor evokes the release of PGE2 and PGI2, NO, and vari-
Neuronal sensitization can occur through changes in the ous cytokines (Leeb-Lundberg et al 2005, Kuhr et al 2010).
level of protein expression, either by transcriptional control There is also immunocytochemical and autoradiographic evi-
altering the production of proteins or by changing the traf- dence that the B1 receptor is expressed in a subset of sensory
cking such that an altered amount of the protein is func- neurons (Wotherspoon and Winter 2000, Ma 2001, Petcu
tionally expressed. Transcriptional control is an important et al 2008) and that the level of expression is increased during
long-term mechanism underlying the effects of neurotrophin inammation (Fox et al 2003). The mechanisms regulating
receptor activation. In some cases, sensitization has been asso- expression of the B1 receptor in sensory neurons are not well
ciated with the de novo expression of molecules important understood but are likely to involve cytokines, as found in

other cell types, and neurotrophins. Functional expression of activation from approximately 42C toward or below normal
sensory neuron B1 receptors is up-regulated by exposure to body temperature via a PKC mechanism (Vellani et al 2001,
the neurotrophins GDNF and neurturin. Under such condi- Sugiura et al 2002).
tions, B1 receptor activation evokes sustained enhancement Activation of TRPV1 cannot explain all the excitatory
of the heat-gated current mediated by TRPV1 (Vellani et al effects of bradykinin inasmuch as activation of vagal and
2004). visceral afferents by bradykinin is retained in TRPV1 knock-
There is good pharmacological evidence that B1 receptors out mice (Kollarik and Undem 2004, Rong et al 2004) and
have an important role in the hyperalgesia associated with per- bradykinin can stimulate DRG neurons from TRPV1/ mice
sistent inammation. Although B1 agonists do not normally (Katanosaka et al 2008). Bradykinin can also act via PLC to
affect nociceptive thresholds in animals, they evoke hyperal- activate TRPA1 (Bandell et al 2004), and bradykinin-evoked
gesia following inammation (Davis and Perkins 1994, Per- responses were signicantly attenuated in sensory neurons
kins and Kelly 1994, Fox et al 2003). Furthermore, peptide from both TRPV1 and TRPA1 knockout mice (Bautista et al
B1 antagonists such as des-Arg10-HOE140 and des-Arg8Leu9- 2006). One possibility is that TRPV1 and TRPA1 act in con-
bradykinin (Perkins and Kelly 1993, Perkins et al 1993, Cam- cert. In this scenario (Bautista et al 2006), activation of PLC
pos and Calixto 1995, Rupniak et al 1997, Fox et al 2003), as evokes TRPV1 gating and calcium inux. Because TRPA1 is
well as non-peptide B1 antagonists (Fox et al 2005, Hawkin- often co-expressed with TRPV1 and because TRPA1 can be
son et al 2007), inhibit thermal or mechanical hyperalgesia activated by increases in the intracellular calcium concentra-
in models of joint, paw, or tail inammation. These data are tion (Doerner et al 2007, Zuborg et al 2007), a small calcium
consistent with the nding that mice lacking the B1 receptor inux through TRPV1 may activate TRPA1.
show reduced thermal (Ferreira et al 2001) and mechanical Failure to inhibit bradykinin responses in all sensory neu-
(Fox et al 2005) hyperalgesia after CFA treatment. rons with staurosporine or prolonged exposure to phorbol
The relative importance of the changes in subtypes of bra- esters (Burgess et al 1989, Rang and Ritchie 1988) suggests
dykinin receptors is variable and depends on the inamma- that excitation can be mediated by a PKC-independent mecha-
tory condition, with evidence of a shift toward a dominant nism. Other evidence points to different phospholipase-linked
role of B1 receptors in chronic conditions in which B1 recep- mechanisms resulting in activation of TRPV1. One proposal
tor expression is up-regulated (see, e.g., Cuhna et al 2007). is that binding of PIP2 to TRPV1 inhibits channel activity
Although many studies have focused on the peripheral role of (Prescott and Julius 2003) and its hydrolysis by B2 receptor
kinin receptors, there is also evidence from studies involving mediated activation of PLC potentiates channel opening by
selective antagonists and knockout mice that B1 and B2 recep- removing this tonic inhibition (Chuang et al 2001). However,
tors expressed in the spinal cord inuence spinal processing of the inhibitory inuence of PIP2 on TRPV1 has been chal-
nociceptive signals in inammatory conditions (Pesquero et al lenged, and there is evidence that PIP2 binding potentiates
2000; Ferriera et al 2001, 2002). rather than inhibits TRPV1 (Klein et al 2008, Yao and Qin
2009, Sowa et al 2010). Phosphoinositide binding may have
Bradykinin Receptor Signaling both inhibitory and potentiating effects on TRPV1, depend-
B1 and B2 receptors couple through Gq to stimulate PLC, ing on the level of stimulation (Lukacs et al 2007).
which results in phosphoinositide hydrolysis, DAG produc- B2 receptor activation also stimulates the 12-lipoxygenase
tion, and mobilization of intracellular Ca2+ from intracellu- pathway and leads to the production of endogenous TRPV1
lar stores. They can also act through Gi to inhibit adenylate agonists (e.g., 12-hydroperoxyarachidonate [HPETE] and leu-
cyclase and stimulate the MAPK pathways (Leeb-Lundberg kotriene B4 [LTB4]. Bradykinin-evoked activation of TRPV1-
et al 2005, Cheng and Ji 2008). A signicant body of evidence like currents, neuronal ring, and behavioral responses are
supports the idea that bradykinin activates sensory neurons blocked by lipoxygenase inhibitors, consistent with a con-
via a DAGPKC pathway. Bradykinin causes the transloca- tribution of this pathway (Shin et al 2002, Carr et al 2003,
tion of a specic PKC isoform, PKC-, from the cytoplasm to Calixto et al 2004, Wu and Pan 2007). Other data point to
the plasma membrane of dorsal root ganglion (DRG) neurons a role of COX products since the COX inhibitor urbipro-
(Cesare et al 1999), and the excitatory effects of bradykinin fen inhibits the heat sensitization induced by bradykinin in a
are inhibited by the PKC inhibitor staurosporine (Burgess et al skinnerve preparation (Petho et al 2001).
1989), which also attenuates the responses of skin afferents Two other ionic mechanisms have recently been proposed
(Dray et al 1992). Furthermore, the bradykinin responses of for bradykinin-evoked activation of DRG neurons. Depolar-
many, but not all, neurons are reduced or abolished when PKC ization resulting from inhibition of M-type potassium cur-
activity is down-regulated by prolonged exposure to phorbol rents and activation of a calcium-activated chloride current,
esters (Rang and Ritchie 1988, Burgess et al 1989). encoded by TMEM16A, have been proposed as important
PKC activators depolarize sensory neurons by opening a PLC-linked mechanisms for the excitatory actions of bradyki-
cation-permeable ion channel (Burgess et al 1989, McGehee nin (Liu et al 2010).
and Oxford 1991), and several pieces of information indi-
cate that bradykinin exerts its effects, in part, by sensitizing Arachidonic Acid Metabolites
or opening the heat-sensitive TRPV1 ion channel. Bradyki-
nin activates ion channels in DRG neurons with properties The enzymatic breakdown of arachidonic acid yields a vari-
similar to those of TRPV1 channels (Premkumar and Ahern ety of bioactive lipid molecules that have diverse physiologi-
2000); this agonistic effect requires the presence of PKC- and cal roles, including important actions in inammation and
is blocked by PKC inhibitors (Cesare et al 1999, Premkumar pain. These molecules are not stored but are synthesized de
and Ahern 2000). Bradykinin also increases the capsaicin sen- novo from membrane lipids. The rst step is release of ara-
sitivity of TRPV1 and reduces the temperature threshold for chidonic acid from phospholipids by the action of PLA2
52 Section One | Neurobiology of Pain

enzymes. Arachidonic acid is then metabolized to prostaglan- and act with some specicity on different prostanoid recep-
dins via the COX enzymes; to leukotrienes, 5-HPETE, and tors, termed EP, DP, and IP, respectively. Each of the pros-
5-hydroxyeicosatetraenoic acid (HETE) via 5-lipoxygenase; tanoid receptors has distinct coupling to G proteins, and the
to 12-HPETE and 12-HETE via 12-lipoxygenase; to lipoxins pattern of coupling determines the biochemical consequence
via 15-lipoxygenase; and to epoxyeicosatetraenoic acids via of receptor activation. Four major types of EP receptors
the action of cytochrome P450. (EP14) have been described, and splice variants of the EP3
subclass have also been identied, which probably explains
Prostaglandins the multiplicity of transduction pathways that have been
Non-steroidal anti-inammatory drugs (NSAIDs), which associated with this receptor. In situ hybridization studies
inhibit COX enzymes, are the most widely used and effec- have shown the presence of mRNA for IP, EP1, EP3, and EP4
tive drugs for the clinical treatment of inammatory pain receptors in DRG neurons. About half the neurons express
and hyperalgesia. NSAIDs have no obvious effect on normal EP3 receptor mRNA; 40%, IP mRNA; 30%, EP1 mRNA; and
pain thresholds but attenuate the abnormal pain responses in 20%, EP4 mRNA, with some degree of co-expression (Sugi-
inammatory conditions. Two COX enzymes, COX-1 and moto et al 1994, Oida et al 1995). Of these, EP1, EP4, IP,
COX-2, are responsible for the rst steps in prostaglandin and some splice variants of EP3 receptors (EP3B and EP3C)
synthesis. These enzymes have two catalytic enzymatic activi- couple positively via Gs to stimulate adenylate cyclase and
ties: a COX activity responsible for the production of PGG2 raise cAMP levels.
from arachidonic acid and a peroxidase activity that reduces A major peripheral effect of PGE2 and PGI2 is to sensitize
PGG2 to form PGH2, the rst steps in prostanoid biosynthesis. afferent neurons to noxious chemical, thermal, and mechani-
In general, COX-1 is considered to have a housekeeping cal stimuli (see, for example, Mizumura et al 1987, Schaible
role in almost all tissues mediating physiological responses. and Schmidt 1988, Birrell et al 1991). In contrast, PGD2
In contrast, COX-2 is not constitutively expressed (except in shows little or no such activity (Rueff and Dray 1992). The
the kidney, vas deferens, and importantly, the brain) but is importance of these receptor subtypes in the periphery is con-
induced in inammatory conditions. In the periphery, COX-2 rmed by the ndings that EP3/ and IP/ mice show reduced
expression is induced in cells involved in inammation (mac- hyperalgesia after lipopolysaccharide (LPS) administration
rophages, monocytes, and synoviocytes) and is primarily (Ueno et al 2001). In contrast, intrathecal administration of
responsible for synthesis of the prostaglandins involved in PGE2 induced normal mechanical allodynia in wild-type and
acute and chronic inammatory states. COX-2 expression EP3/ mice but not in EP1/ mice, thus illustrating that the
is induced in peripheral tissues in animal models of arthri- EP1 receptor plays a role in prostaglandin-induced spinal sen-
tis, and up-regulated expression is seen in human rheuma- sitization (Minami et al 2001).
toid arthritic joints, although relatively little expression has
been noted in human osteoarthritic joints. Both COX-1 and Lipoxygenase Products
COX-2 are expressed constitutively in DRG neurons and in The potential role of lipoxygenase products in inammatory
the spinal cord. Normally, COX-1 is expressed in small and pain is less clear, and although the levels are increased in
medium-sized DRG neurons and in neurons and astrocytes in inammatory conditions, evidence of a direct role in nocicep-
the spinal cord. Enzyme expression in both neuronal and non- tion is lacking. The major effect of these lipids is to recruit
neuronal cells in the spinal cord is up-regulated after periph- immune cells and alter microvascular permeability. Intrader-
eral inammation and nerve injury (see Samad et al 2002, mal injection of LTB4 or 8R,15S-diHETE decreases mechani-
Svensson and Yaksh 2002), and intraspinal release of PGE2 cal and thermal thresholds in rats (Levine et al 1984, 1985,
is enhanced during peripheral inammation (Yang et al 1996, 1986a; Martin et al 1987; Martin 1990) and humans (Bis-
Ebersberger et al 1999). gaard and Kristensen 1985), and LTB4 sensitizes dental affer-
The important roles of spinal cord COX enzymes are not ents (Madison et al 1992). The sensitizing actions of LTB4
discussed in detail here but are covered in Chapter 28. The require the presence of polymorphonuclear (PMN) leukocytes
available information indicates that COX inhibition at both and are thus likely to be indirect (Levine et al 1984, 1985).
peripheral and central sites can contribute to the anti-hyper- 8R,15S-diHETE reduces the thermal and mechanical thresh-
algesic effects, with the predominant clinical effect being olds of C bers (Taiwo et al 1989, White et al 1990) and
mediated centrally. Certainly, prostaglandins produced in the excites some C-ber neuromas (Devor et al 1992). A role of
periphery after tissue injury can sensitize peripheral nerves LTB4 in experimental antigen (ovalbumin)-induced mechani-
and induce hyperalgesia in animal models of inammation, cal hyperalgesia has been shown by using the LTB4 antagonist
thus suggesting that a component of hyperalgesia could be CP10596 (Cunha et al 2003). More recently, the cysteinyl-
due to a peripheral action. However, the nding that intra- leukotriene receptor CysLT2 was found to be expressed in
thecal administration of COX-2selective inhibitors sup- about 40% of rat DRG neurons, preferentially in small-
presses experimentally induced inammatory hyperalgesia diameter neurons. Intraplantar administration of the CysLT2
also argues for a central site of action (Samad et al 2001). agonist LTC4 strongly enhanced the nocifensive response
The observations that COX-2 inhibitors have clinical ef- evoked by the P2X3 agonist -me-ATP but was without
cacy similar to that of non-selective NSAIDs and that COX-2 effect on thermal sensitivity, thus suggesting a lack of effect
inhibitors exert a rapid effect after surgery also argue that on TRPV1 channels (Okubo et al 2010).
they act in these conditions at central sites where COX-2 is One probable action for some lipoxygenase products
constitutively expressed. is to activate TRPV1 channels inasmuch as 12S-HPETE,
PGH2 is metabolized by different prostaglandin synthe- 15S-HPETE, 5S-HETE, and LTB4 all open TRPV1 channels
tases to a range of prostaglandins. Prostaglandins such as in DRG neurons (Hwang et al 2000). The behavioral effects
PGE2, PGD2, and PGI2 are produced during inammation of 8R,15S-diHETE noted earlier are unlikely to be due to such

an action since this lipid shows very weak agonist effects on by short synthetic peptides based on the sequence of the teth-
TRPV1. ered ligands of the different PARs. PAR1, PAR3, and PAR4
are activated by thrombin produced during the blood-clotting
Other Fatty Acid Metabolites cascade, whereas PAR2 activation is triggered by tryptase,
In addition to the leukotrienes, lipoxygenases can also con- which is known to be released from mast cells in inamma-
vert eicosapentaenoic and docosahexaenoic acids into active tory conditions, as well as by the blood-clotting factors VIIa
signaling molecules. Formation of some of these metabo- and Xa and the cysteine protease cathepsin S (Soh et al 2010,
lites requires the sequential action of COX-2 or cytochrome Cattaruzza et al 2011). In this way PARs are activated as a
P450 followed by lipoxygenase-mediated oxidation (Bannen- result of tissue damage and inammation. Because activation
berg and Serhan 2010). The resulting molecules have been involves an irreversible enzymatic cleavage, restoration of
named resolvins because of the roles that they are thought to PAR sensitivity requires internalization of the receptors and
play in the resolution phase of inammation, and they have insertion of new receptor into the plasma membrane.
attracted interest for their analgesic potential (Ji et al 2011).
The resolvins RvE1 and RvD1 potently reduce thermal and Protease-Activated Receptor Signaling
mechanical hypersensitivity in inammatory pain models. Activation of PARs can trigger a variety of intracellular sig-
Resolvins produce these effects by stimulating Gi/o-coupled naling pathways. PAR1 and PAR2 couple to either Gq/11,
GPCRs located both on DRG neurons and in the spinal cord, G12/13, or Gi; PAR3 signals through Gq/11 activation; and
thereby effectively inhibiting the activity of the sensory neuron PAR 4 through either Gq/11 or G12/13 (Russo et al 2009,
ion channels TRPA1 and TRPV1, as well as C-ber evoked Soh et al 2010). In this way, activation of PAR1 and PAR2
long-term potentiation in the spinal cord (Xu et al 2010, Park may stimulate PLC- to activate the DAGPKC and IP3Ca2+
et al 2011). pathways (Gq11), Rho and Rho-kinase (G12/13), and the
Linoleic acid is converted into several hydroxyl and car- MAPK cascade and inhibit adenylate cyclase (Gi).
bonyl derivatives (9-HODE, 13-HODE, 9-oxoODE, and
13-oxoODE) by both lipoxygenase pathways and non- Protease-Activated Receptor Expression
enzymatic lipid peroxidation reactions. In experimental PARs were initially detected in platelets, endothelial cells, and
situations, formation of these mediators is increased by broblasts, but they are also expressed in the nervous sys-
depolarization of the spinal cord with a high-K+ solution tem. All four PARs are expressed on peripheral sensory neu-
(Patwardhan et al 2009). Extended exposure to heat also rons. Expression of PAR2 is almost exclusively restricted to
signicantly increases the tissue concentration of these oxi- small-diameter unmyelinated neurons in rat and mouse DRG
dized linoleic acid metabolites in mouse skin biopsy samples. neurons, a majority of which are also positive for calcitonin
Application of 9-HODE to cultured trigeminal neurons stim- generelated peptide (CGRP) expression (Zhu et al 2005, Vel-
ulates TRPV1, and administration in vivo evokes nocifensive lani et al 2010).
behavior and thermal hypersensitivity, which is absent in Studies using PAR subtypeselective peptide agonists and
Trpv1/ mice, thereby demonstrating that TRPV1 mediates knockout mice suggest that the hyperalgesic effect of PAR
the nociceptive effect of 9-HODE (Patwardhan et al 2010). activation is mediated primarily through PAR2, although
Thus, oxidized linoleic acid metabolites, such as the endo- in vitro, PAR1 and PAR4 receptor activation can sensitize
cannabinoid anandamide and several lipoxygenase products TRPV1-mediated heat responses (Vellani et al 2010). Intra-
formed from arachidonic acid, can act as direct TRPV1 ago- plantar injection of PAR2 synthetic agonists, as well as tryp-
nists (Zygmunt et al 1999, Hwang et al 2000). tase, evokes prolonged thermal and mechanical hyperalgesia
During conditions characterized by oxidative stress, such and c-fos expression in laminae I and II in the spinal cord
as inammation or reperfusion after ischemia, a range of lipid (Kawabata et al 2001, 2002; Vergnolle et al 2001). This
peroxidation products are formed in reactions between free hyperalgesia occurs with low concentrations of agonists that
radicals and membrane lipids. Many of the lipids formed are do not cause overt inammation, and it is not seen in mice
well-known reactive, electrophilic molecules that bind cova- lacking the neurokinin 1 (NK1; substance P) receptor or in
lently to proteins such as hydroxynenonal, cyclopentenone the presence of centrally acting NK1 receptor antagonists.
prostaglandins, isoprostanes, and related species. The cova- Mast cells are known to be closely associated with sensory
lent modication of redox-sensitive transcription factors ini- nerves in normal as well as inammatory conditions (Stead
tiates specic signaling cascades that may act to modify or et al 1997), and the hyperalgesia evoked by the mast cell
protect against oxidative conditions, but the electrophilic lip- degranulating agent 48/80 is signicantly reduced in PAR2/
ids also stimulate nociceptive sensory neurons directly by acti- mice (Vergnolle et al 2001). These ndings suggest a direct
vating TRPA1 (Trevisani et al 2007, Andersson et al 2008). action of PAR2 activation on sensory nerve function. Such a
direct action has been demonstrated in isolated DRG neurons,
where activation of PAR2 sensitizes TRPV1 and TRPA1 to
Protease-Activated Receptors
agonist stimulation. The sensitizing effect of PAR2 activation
Four types of G proteincoupled protease-activated recep- on TRPV1 appears to be mediated by PKC since it is inhibited
tors (PARs) have been identied (PAR14). These receptors by PKC inhibitors and a PKC- translocation inhibitor (Ama-
are activated by a unique mechanism whereby extracellular, desi et al 2004, Dai et al 2004). In contrast, PAR2-mediated
soluble, or surface-associated proteases cleave at specic resi- sensitization of TRPA1 is independent of PKC and instead
dues in the extracellular N-terminal domain of the G protein depends on activation of PLC and subsequent reduction of
to expose a novel N-terminal sequence that acts as a teth- PIP2 levels (Dai et al 2007). In vivo, administration of a selec-
ered ligand and activates the receptor by binding to other tive PAR2 agonist enhances the nocifensive responses evoked
regions of the protein. These agonist effects can be mimicked by the TRPA1 agonists AITC and cinnamaldehyde in the rat
54 Section One | Neurobiology of Pain

(Dai et al 2007). An important role for TRPV1 in vivo is also the sensitization mechanism or mechanisms may be attribut-
shown by the nding that the thermal hyperalgesia, mechani- able to PKC-mediated modulation of ion channels.
cal allodynia, and spinal cord c-fos expression evoked by the Relatively few data are available on the roles of periph-
intraplantar injection of a PAR2 agonist peptide are signi- eral 5-HT4 and 5-HT7 receptors in inammatory condi-
cantly attenuated in TRPV1/ mice (Amadesi et al 2004, Dai tions, although some pharmacological evidence indicates that
et al 2004). these receptor subtypes have roles in the longer-term (days)
Activation of PAR1 may have complex effects on nocicep- mechanical allodynia following intraplantar administration
tion. Sub-inammatory doses of PAR1 agonists have been of formalin (Godinez-Chapiro et al 2011). These receptors are
reported to increase nociceptive thresholds and signicantly positively coupled to adenylate cyclase, and receptor activa-
reduce the inammatory hyperalgesia induced by carrageenan tion stimulates cAMP production. An increase in cAMP can
(Asfaha et al 2002). However, higher doses of PAR1 agonists result in a PKA-mediated modication of ion channel function,
are pro-nociceptive, and it is possible that stimulation of PAR1 notably, increased activity of tetrodotoxin (TTX)-resistant
on different neuronal populations (small TRPV1-containing sodium channels (Cardenas et al 2001, Scroggs 2011).
nociceptors and larger non-nociceptive neurons) can explain
these apparently contradictory observations (Vellani et al Nitric Oxide
2010). The pro-nociceptive effect of PAR1 stimulation appears
to depend on PKC- and sensitization of TRPV1. Although the actions of NO on nociceptive processes are pri-
marily spinal and evident after intrathecal administration of
drugs, there is controversial evidence of a peripheral action
of NO. The cellular source of NO is unclear, and both neu-
Serotonin is one of many mediators released from platelets ronal and non-neuronal sources are likely. NO is produced in
(rats and humans) and mast cells (rats) in injured and inamed the periphery during inammation (see Toriyabe et al 2004).
tissues. In humans, intradermal dialysis of 5-hydroxytryptamine nNOS appears to be responsible for synthesis in the early
(5-HT) evokes burning pain (Lischetski et al 2001), and intra- phase of inammation and nNOS and iNOS at later phases
muscular injection of 5-HT elicits pain and sensitization to (Omote et al 2001). Experimentally, intradermal and intra-
pressure stimuli (Ernberg et al 2000, Ernberg et al 2006). In vascular injection of NO evokes a concentration-dependent
situ hybridization studies have shown that DRG neurons nor- pain in human volunteers (Holthusen and Arndt 1994, 1995),
mally express mRNA for 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, whereas topical administration of NO donors is antinocicep-
5-HT3B, and 5-HT4 receptors (Nicholson et al 2003), with tive. The site of action appears to be important. Studies in
other evidence for the expression of 5-HT7 receptors (Amaya- rats have shown that intradermal administration of the NO
Castellanos et al 2011). Expression of some of these recep- precursor l-arginine or an NO donor (3-[4-morphinolinyl]-
tor subtypes (5-HT2A, 5-HT3, 5-HT4, and 5-HT7) is increased sydnonimine hydrochloride [SIN-1]) evokes mechanical
with inammation (Wu et al 2001, Liu et al 2005). hypersensitivity. In contrast, subcutaneous injection of
Some of the excitatory actions of serotonin have been these agents had little effect on baseline mechanical thresh-
ascribed to activation of the 5-HT3 receptor/ion channel. olds but reversed PGE2-induced hypersensitivity (Vivancos
5-HT3 receptor agonists enhance the excitability of unmy- et al 2003) via an NO/cGMP pathway (Sachs et al 2004).
elinated C-bers (Moalem et al 2005, Lang et al 2006), and A pro-nociceptive action of NO in inammatory conditions
relatively selective 5-HT3 antagonists reduce the pain evoked is supported by the nding that local administration of the
by peripheral administration of serotonin or carrageenan in NOS inhibitor N-nitro-l-arginine methyl ester (l-NAME)
rats (Eschalier et al 1985, Richardson et al 1985, Sufka et al reduces both mechanical and thermal hyperalgesia, as well as
1992). the inammation induced by carrageenan (Lawand et al 1997,
Serotonin can also activate and sensitize nociceptors by Nakamura et al 1996). Similarly, co-injection of another
actions on G proteincoupled 5-HT receptors. 5-HT2A recep- NOS inhibitor, NG-methyl-l-arginine (l-NMA), inhibited
tors are expressed mainly in small-diameter (A- and C-ber) PGE2-induced mechanical hyperalgesia, whereas intradermal
peptidergic and non-peptidergic sensory neurons, and there injection of the NOS substrate l-arginine or the NO donor
is signicant overlap with TRPV1 expression (Okamoto et al SIN-1 evoked mechanical hyperalgesia (Aley et al 1998). In
2002, van Steenwinckel et al 2009). 5-HT2A receptors play peripheral nerves the NO-sensitive (soluble) guanylate cyclase
a signicant role in inammatory thermal hypersensitivity. is expressed by non-neuronal cells and not by sensory neu-
Intraplantar administration of 5-HT2A agonists into rats pro- rons (Schmidtko et al 2007), so the sensory neuron effects of
duces thermal hyperalgesia (Abbott et al 1996, Tokunaga et al activating the NO/cGMP pathway are likely to be indirect.
1998), and activation of peripheral 5-HT2A receptors induces NO can also nitrosylate ion channels, and this may be a more
Fos expression in dorsal horn neurons, indicative of sensory important mechanism for any direct pro- or antinociceptive
neuron excitation (Doi-Saika et al 1997). Conversely, periph- NO effects. NO can stimulate DRG neurons by activation of
eral administration of 5-HT2A receptor antagonists reduces both TRPA1 and TRPV1, and studies of genetically modied
the thermal hyperalgesia induced by either CFA or carra- mice show that the thermal hyperalgesia elicited by injection
geenan (Okamoto et al 2002, Wei et al 2005, Huang et al of an NO donor is largely dependent on TRPV1 expression.
2009). In addition to the strong evidence for a role of 5-HT2A In addition, both TRPA1 and TRPV1 appear to play roles in
receptors, there is also pharmacological evidence that 5-HT2B the acute nociceptive behavioral response to NO donor injec-
receptors play a role in inammatory mechanical hypersen- tion after pre-activation of the PLC/PKA pathways (Miya-
sitivity but not in thermal hyperalgesia (Lin et al 2011). The moto et al 2009). Conversely NO activates ATP-sensitive
cellular mechanisms responsible for these effects are unclear. K+ channels (Kawano et al 2009) and inhibits voltage-gated
5-HT2 receptors are usually linked to the PLC pathway, and sodium channels (Renganathan et al 2002) in DRG neurons;

both actions will inhibit neuronal ring and could contribute AF-353) (Jarvis et al 2002, Oliveira et al 2009, Ford 2012).
to antinociception. Many of the peripheral effects of NO or AF-353 is also effective in models of bone cancer pain, where
NOS inhibition are likely to involve other cells and mediators, it reversed mechanical hypersensitivity and improved weight
including alterations in cytokine levels (Chen et al 2010b). bearing on the affected limb (Kaan et al 2010). The marked
effects of antisense oligonucleotide treatment and pharmaco-
logical antagonism contrast with the relatively mild pheno-
ATP and Adenosine
typic changes seen in P2X3-null mice (Cockayne et al 2000,
ATP, P2X, and P2Y Receptors Souslova et al 2000), which display a modest reduction in
There has been considerable debate about the role of ATP the behavioral response to intraplantar administration of
in activation of peripheral nerves, especially in inammatory formalin. The paradoxical nding that P2X3-null mice show
conditions. ATP is released from damaged cells, and ATP increased thermal hyperalgesia after injection of CFA suggests
levels are elevated in damaged and inamed tissues (Gordon that some adaptive processes occur when the P2X3 receptor
1986, Cook and McCleskey 2002). It has also been pro- is ablated.
posed that ATP has a role in the genesis of pain associated
with malignancy inasmuch as ATP levels at tumor sites are P2Y Receptors
higher than those in normal tissues (Pellegatti et al 2008). In ATP can also stimulate sensory neurons by activating G
humans, application of ATP to the skin evokes the sensation proteincoupled P2Y receptors. Of the known P2Y receptors,
of pain (Bleehen and Keele 1977, Coutts et al 1981), which is mRNA for the Gq/11-linked receptors P2Y1, P2Y2, P2Y4, and
enhanced after ultraviolet irradiation (Hamilton et al 2000), P2Y6 is expressed in sensory ganglia. P2Y1 and P2Y2 recep-
and intracutaneous administration of ATP excites human C tors, which are expressed by sensory neurons (Molliver et al
bers (Hilliges et al 2002). Similar pain behavior has been 2002, Kobayashi et al 2006), have received the most attention.
noted in animals, with nocifensive behavior being evoked by Expression of P2Y2 is increased during inammation induced
intraplantar administration of ATP (Bland-Ward and Hum- by CFA, whereas P2Y1, P2Y4, and P2Y6 are reduced (Malin
phrey 1997, Hamilton et al 1999, Jarvis et al 2001), and this et al 2008). Both P2Y1 and P2Y2 receptors are Gq11 linked
is augmented by treatment with PGE1 and the inammatory and signal via IP3DAG pathways, which is consistent with
agent carrageenan (Sawynok and Reid 1997, Hamilton et al the nding that activation of either receptor subtype evokes a
1999). These behavioral responses are probably mediated by rise in intracellular calcium levels and an increase in excitabil-
A and C bers because these bers are excited by ATP both ity in DRG neurons that is blocked by PLC and PKC inhibi-
in vivo (Dowd et al 1998) and in isolated nerve preparations tion (Usachev et al 2002, Malin and Molliver 2010, Yousuf
(Hamilton et al 2001) and the pain response evoked by ATP in et al 2011). On the other hand, stimulation of the Gi/o-coupled
human skin is markedly reduced after the topical application receptors P2Y1214 reduced the excitation of DRG neurons in
of capsaicin to functionally desensitize the TRPV1-expressing a pertussis toxinsensitive fashion. In vivo, peripheral admin-
bers (Hamilton et al 2000). istration of P2Y13 and P2Y14 agonists reduced the inamma-
The receptors responsible for this excitation are likely to tory hyperalgesia induced by CFA (Malin and Molliver 2010).
contain the P2X3 receptor subtype (i.e., P2X3 homomeric P2Y receptor activation in DRG neurons also activates the
or P2X2/3 heteromeric receptors) because sensory bers are transcription factor cAMP response elementbinding protein
excited by the P2X3 agonist ,-me-ATP (see Irnich et al (CREB), which is likely to lead to longer-term changes in the
2002). Furthermore, P2X3 receptor expression is restricted cell phenotype (Molliver et al 2002). P2Y receptor activation
to small-diameter sensory afferents (Vulchanova et al 1997, by the P2Y2/P2Y4 agonist uridine triphosphate (UTP) evokes
Bradbury et al 1998), and their expression is up-regulated in sustained action potential ring in capsaicin-sensitive C bers
experimental inammatory conditions (Xu and Huang 2002, and some A bers (Stucky et al 2004). This effect is probably
Shinoda et al 2005). One mechanism for this up-regulation is mediated through P2Y2 receptors since these receptors appear
an increased supply of the growth factors NGF and GDNF to be expressed at very low levels by sensory neurons (Sanada
in sensory nerves during inammation since administration et al 2002).
of both these growth factors (by intrathecal administration) The mechanisms underlying P2Y receptormediated excita-
increased P2X3 receptor immunoreactivity in rat DRG neu- tion involve sensitization of TRPV1 and modulation of ion
rons (Ramer et al 2001). Similarly, P2X3 receptor expression channels that regulate the ring frequency of action potentials.
is elevated following injection of NGF into skeletal muscle P2Y2 receptor activation potentiates the capsaicin-evoked
(Liu et al 2011). Inammatory mediators may also increase TRPV1 currents and [Ca2+]i responses in isolated sensory neu-
ATP sensitivity via PKA- and PKC-mediated phosphorylation rons, and this potentiation is lost in P2Y2-null mice (Mori-
of P2X3-containing receptors (Paukert et al 2001, Fabbretti yama et al 2003, Malin et al 2008). P2Y1 receptor activation
et al 2006). also lowers the heat activation threshold for TRPV1 in rat
A role of P2X3 receptors in inammatory pain is sup- DRG neurons (Tominaga et al 2001) and increases sensitivity
ported by the nding that intrathecal delivery of antisense to the TRPV1 agonist capsaicin (Yousuf et al 2011).
oligonucleotides or small interfering RNA (siRNA) directed P2Y1/2 receptor activation can also increase the excitability
against P2X3 mRNA, which reduces P2X3 protein expression of DRG neurons by inhibiting Kv7 potassium channels (You-
by about 50%, partially reverses inammatory thermal and suf et al 2011), which is also a mechanism described for bra-
mechanical hyperalgesia (Barclay et al 2002, Honore et al dykinin sensitization. Furthermore, P2Y2 activation sensitizes
2002, Dorn et al 2004). In addition, reversal of inamma- mechanotransduction channels (Lechner and Lewin 2009)
tory thermal and mechanical hyperalgesia, as well as thermal and purinergic P2X2 and P2X3 channels (Chen et al 2010a)
and mechanical hyperalgesia after nerve injury, is seen after and may underlie the ATP-induced potentiation of TTX-
the administration of selective antagonists (A317491 and resistant sodium channel (Nav1.8) currents (Baker 2005).
56 Section One | Neurobiology of Pain

Adenosine such as skin (Deval et al 2008) and skeletal muscle (Sluka et al

It is almost certain that some of the effects of ATP in vivo 2003). Finally, low pH can augment or stimulate neuronal
are mediated by adenosine diphosphate (ADP) (Bleehen and ring by inhibiting K+ channel activity (Baumann et al 2004).
Keele 1977, Coutts et al 1981), AMP, and adenosine (Bleehen
and Keele 1977) formed by rapid sequential ectonucleotidase
cleavage of ATP. All these agents produce pain when applied
to human skin. However, the underlying mechanisms prob- It is now well established that the immune system, as well
ably differ because the nocifensive response to ADP seen in as the factors that it produces, can alter sensory processing
animal studies differs from that evoked by ATP (Bland-Ward and play a pivotal role in the development and maintenance
and Humphrey 1997). of persistent pain (Marchand et al 2005, Ren and Dubner
During inammation, adenosine is released from a variety 2010). For example, not only are cytokines and chemokines
of cell types (endothelial cells, mast cells, neutrophils, and an important means of communication between immune cells,
broblasts), in addition to release from neurons. The effects of but such factors can also act as pain mediators and have a
adenosine are complex, with evidence of both pro-nociceptive direct sensitizing action on nociceptors. The importance of
and analgesic effects (see Sawynok and Liu 2003) mediated the immune system is not restricted to inammatory pain
through various receptor subtypes (A1, A2A, A2B, and A3) at states but extends to neuropathic conditions since nerve injury
peripheral and spinal sites. Although some of the effects are evokes a profound immune response. Many of the pain media-
probably directly on nerves, others are more likely to be tors discussed below are closely linked to this system through
mediated via activation of adenosine receptors on other cell either their release by or their action on different immune cells.
types, such as mast cells. Nevertheless, there is clear evidence We discuss the role of particular immune cells in different pain
that adenosine can activate sensory nerves since intravenous states below and summarize these actions in Table 3-1.
administration of adenosine produces pain in human volun-
teers (Sylven 1989) and application of adenosine sensitizes cat
Mast Cells
myelinated and unmyelinated vagal afferents (Cherniak et al
1987). Isolated segments of human nerve are also depolarized Mast cells are found in areas of the body that interact with
by ATP; the pharmacological properties are consistent with an the external environment, such as the skin and mucosal
effect mediated by adenosine acting on Gs-coupled A2B receptors layers, and these cells are normally situated in close
(Irnich et al 2002). In other experiments, A1 agonists have been
reported to activate C bers in the rat (Esquisatto et al 2001,
Sawynok et al 2000), and stimulation of A1 receptors induces Table 3-1 Contribution of Peripheral Immune Cells
an inward current and action potential ring in guinea pig to Animal Models of Persistent Pain
jugular and spinal esophageal TRPV1-positive nociceptors (Ru INFLAMMATORY
et al 2011). In contrast to the predominating pro-nociceptive CELL TYPE* PAIN NEUROPATHIC PAIN
peripheral effects produced by adenosine, intrathecal admin- Macrophage Inltration (joint, Inltration (nerve)
istration of adenosine has well-recognized analgesic effects muscle) / Mechanical,
Mechanical, /thermal,
mediated by A1 receptor activation (Sawynok and Liu 2003). spontaneous spontaneous
Accordingly, intrathecal administration of the ectonucleotidase
prostatic acid phosphatase (PAP) has been shown to produce Dendritic cell/ Inltration/activation
Langerhans cell (skin, nerve)
long-lasting antinociception and anti-hyperalgesia mediated by
hydrolysis of extracellular AMP to adenosine, which in turn Mast cell Degranulation (skin) Degranulation (skin,
Mechanical, thermal, nerve)
stimulates adenosine A1 receptors (Zylka et al 2008). spontaneous, visceral Mechanical, thermal
Neutrophils Inltration (skin, Inltration (nerve)
Low pH joint) Thermal
Mechanical, thermal
The pH of the extracellular environment is known to fall in
a number of pathophysiological conditions, such as hypoxia T cells Inltration (joint) Inltration (nerve)
Mechanical Mechanical, thermal
and anoxia, as well as with inammation and tumors. Acidic
conditions can have direct effects on sensory nerves. Low- Natural killer cells Inltration (nerve)
pH solutions evoke prolonged activation of sensory nerves B cells Inltration (nerve)
and produce a sharp stinging pain in humans (Lindahl 1962, Mechanical
Steen and Reeh 1993, Jones et al 2004). Several mechanisms This table highlights the involvement of immune cells in both inammatory and
are thought to underlie the neuronal excitation observed. neuropathic pain by using data from animal models. Following the injection of an
inammogen or damage to a peripheral nerve (either traumatic or drug induced),
One key effect of acid solutions is activation and sensitiza- various immune cells inltrate the relevant peripheral tissue and/or alter their
tion of the thermosensitive ion channel TRPV1 (Tominaga response state. In addition, via genetic, chemical, or pharmacological approaches,
et al 1998, McLatchie and Bevan 2001, Lefer et al 2006). certain immune cell populations can be depleted, their inltration suppressed, or their
activation prevented, thereby leading to the attenuation of persistent pain. The data in
A second mechanism is direct activation of ASICs (see Deval this table is a summary of the studies discussed in this section.
et al 2010), notably ASIC3, which is expressed in the sensory *Although microglia are important in the development and/or maintenance of
persistent pain, they are central nervous system immune cells and therefore have not
innervation of the heart and activated by modest reductions in been mentioned in this table. Work regarding these cells is discussed in Chapter 4.
extracellular pH (to about pH 7). ASIC3 has been proposed to Inammatory models include complete Freunds adjuvant, carrageenan, zymosan,

be the sensor in cardiac nociceptors that triggers cardiac pain nerve growth factor, lipopolysaccharide, formalin, collagen- or antigen-induced
arthritis, and acetic acid.
in response to myocardial acidity (Sutherland et al 2001) and Neuropathic pain models include partial sciatic nerve ligation, chronic constriction

may play a role in sensing acidic conditions in other tissues injury, spinal nerve ligation, spared nerve injury, vincristine, paclitaxel, and streptozocin.

proximity to blood vessels and nerves. Mast cell granules hypersensitivity and neutrophil inux (Ting et al 2008). The
contain numerous chemicals, including histamine, and they chemokine receptors CXCR1 and CXCR2 are both important
can also synthesize and release many cytokines and chemo- in neutrophil migration and activation in numerous inam-
kines (Metcalfe et al 1997). matory states (Bizzarri et al 2006). Dual inhibition of these
Mast cells can be degranulated by the compound 48/80, receptors was able to signicantly reduce the accumulation
which when applied to human skin causes thermal hyperalge- of neutrophils and abnormal sensory behavior induced by
sia, thus indicating that chemicals in the granules of mast cells zymosan, carrageenan, and LPS (Cunha et al 2008a). More
are pro-algesic (Drummond 2004). Chronic treatment with recently, specic antagonism of the CXCR2 receptor via the
this compound prevents re-granulation of these cells, and in small molecule SB225002 reduced both pain-related hypersen-
this state some common models of inammatory pain, includ- sitivity and neutrophil accumulation in the carrageenan model
ing those precipitated by injection of acetic acid or zymosan (Manjavachi et al 2010). Other factors with strong chemo-
and the second phase of the formalin test, show reduced pain- tactic effects on neutrophils include the lipoxygenase product
like behavior (Ribeiro et al 2000, Parada et al 2001). Treat- LTB4 (Ford-Hutchinson et al 1980). Both pharmacological and
ment with 48/80 to deplete mast cell granules also reduces genetic inhibition of the action of LTB4 reduced the hypersen-
both the thermal and mechanical hyperalgesia produced by sitivity produced by joint inammation (Guerrero et al 2008).
CFA (Woolf et al 1996). One of the mechanisms by which In agreement with these data, chemical depletion of neutro-
NGF induces thermal hyperalgesia (see below) is thought to be phils decreased their accumulation in skin after both zymosan
mediated via its action on mast cells (Lewin et al 1994). Thus, and carrageenan treatment and prevented full development
NGF was not able to sensitize nociceptors to thermal stimuli of the abnormal sensory behavior in these models (Ting et al
in mice decient in these cells (Rueff and Mendell 1996), and 2008). Although recruitment of these cells is important, block-
these mice do not fully develop pain-like symptoms in a model ade of the C5a receptor in the LPS and carrageenan models did
of cystitis, which also seems to be strongly dependent on the not affect neutrophil recruitment but did attenuate pain-like
release of mast cell mediators (Rudick et al 2008). behavior, thus suggesting that certain molecules such as C5a
Mast cells are also present in the sciatic nerve. Following may, in some instances of inammation, be more important
partial sciatic nerve ligation (PSNL, a model of neuropathic for activation than for direct recruitment of these cells (Ting
pain), very few intact mast cells remain at the site of injury et al 2008). In nave animals, intradermal injection of neu-
or directly distal to it, thus suggesting that the majority have trophil chemotactic factors such as LTB4, N-formylmethionyl-
released the contents of their granules. Stabilization of these leucyl-phenylalanine (fMLP), C5a, and chemokine C-X-C
cells increases the presence of intact mast cells and reduces motif ligand 1 (CXCL1) induces pain-related hypersensitivity
the development of both mechanical and thermal hyperalge- (Levine et al 1985, 1986a; Cunha et al 2008a). Interestingly
sia (Theodosiou et al 1999, Zuo et al 2003). Although the the prominent pro-algesic properties of NGF are also reported
chemicals released by mast cells may act directly to sensitize to depend on neutrophil recruitment (Bennett et al 1998b).
nociceptors, such agents may also act to recruit and activate Recently, IL-17 has been shown to be a pro-nociceptive cyto-
other immune cells within the injured nerve. Histamine is one kine, particularly in the setting of antigen-induced arthritis,
of the mediators released by mast cells. However, the analge- where neutralization of its effect reduced pain-related hyper-
sic effect of antihistamine treatment is modest, and in some sensitivity and neutrophil recruitment in a TNF-dependent
neuropathic pain models such agents have limited effects on manner (Pinto et al 2010). In addition, intraplantar injection
mechanical painrelated hypersensitivity. Stabilization of of this cytokine produces both thermal and mechanical hyper-
mast cells with cromoglycate can reduce neuropathic hyper- sensitivity associated with the accumulation of neutrophils in
sensitivity. Some of this action is likely to be indirect since the dermis (Kim and Moalem-Taylor 2011b, McNamee et al
such treatment also reduced both neutrophil and macrophage 2011). However, it must be stated that neutrophil attraction
inltration into the injured nerve (Zuo et al 2003). Mast cells alone may not be sufcient to cause pain-like behavior because
can produce NGF (Leon et al 1994), and this might also con- the activation status of these cells is also likely to be impor-
tribute to the pro-algesic action of these cells. tant. The chemotactic factor glycogen results in neutrophil
recruitment but does not cause any signicant pain-like hyper-
sensitivity (Levine et al 1985). Nevertheless, systemic deple-
tion of neutrophils signicantly reduced the pain-like behavior
Neutrophils are PMN granulocytes and make up around elicited by LTB4, C5a, fMLP, and NGF administration, thus
60% of the circulating white blood cells, which puts them in suggesting that activated neutrophils are crucial in the pro-
an ideal position to react, in large numbers, to pathogens or algesic properties of these and other factors (Levine et al 1985,
tissue injury. Rodent models of inammatory pain are com- 1986a; Bennett et al 1998b; Ting et al 2008). In vitro experi-
monly induced by the local injection of an antigen, such as ments have shown that in a co-cultured system, dissociated
zymosan, LPS, or carrageenan, and subsequent activation of DRG neurons increase their excitability following neutrophil
the innate and adaptive immune system (Cunha et al 2008a, activation, which suggests that neutrophils do release factors
2008b; Guerrero et al 2008; Ting et al 2008). Accumulation of that can act directly on nociceptive neurons (Shaw et al 2008).
neutrophils occurs in all these models and can be reduced by Clinically, it seems that neutrophils play an important role in
blocking receptors that mediate the rolling, attachment, and inammatory diseases; in particular, they are present in the
transmigration of these cells from blood into tissue. Comple- joint uid and synovial membrane of patients with rheuma-
ment component 5a (C5a), a complement activation product, toid arthritis (RA) (Wright et al 2010). Interestingly, therapies
is a potent chemotactic factor for neutrophils (Shin et al 1968). used to treat RA, such as antibodies against TNF-, reduce
Following injection of zymosan into the paw, pharmacologi- pain scores in these patients and decrease the inux of neutro-
cal inhibition of the C5a receptor attenuated both mechanical phils into the joint (den Broeder et al 2003).
58 Section One | Neurobiology of Pain

Neutrophils are normally completely absent from the nave Macrophages have an important role in the development
sciatic nerve. However, in animals in which the nerve has and maintenance of neuropathic pain. Traumatic injury to a
been injured to induce neuropathic painlike behavior, sub- peripheral nerve results in degeneration of axons separated
stantial neutrophil inltration takes place (Perkins and Tracey from their cell bodies and breakdown of the associated myelin
2000, Zuo et al 2003, Kim and Moalem-Taylor 2011a). In sheath in a process termed wallerian degeneration. Macro-
addition, cytokine recruitment of neutrophils into the non- phages have an important role in phagocytosing and clear-
injured nerve can recapitulate this pain-like behavior (Kim ing myelin debris; because such debris is inhibitory to axon
and Moalem-Taylor 2011b). Some of the strongest evidence regeneration, clearance is vital for effective nerve repair.
for a role of these cells in the development of neuropathic Chronic constriction injury (CCI) of the sciatic nerve in mice
painlike behavior comes from depletion studies. Systemic results in an increase in macrophage inltration over a 28-day
depletion of neutrophils before injury reduced the develop- period that is strongly associated with neuropathic painlike
ment of thermal hypersensitivity (Perkins and Tracey 2000). behavior (Myers et al 1996). Naturally occurring mutant
However, an attempt to deplete neutrophils 8 days after injury mice that exhibit slow wallerian degeneration display delayed
had no effect on pain behavior (Perkins and Tracey 2000), a macrophage recruitment and reduced cytokine production in
nding suggestive of an important role in the initiation rather injured nerves (Sommer and Schafers 1998). Consistent with
than the maintenance of neuropathic pain. Neutrophils can this attenuated inammatory response, such mice also show
release numerous chemokines (Scapini et al 2000), and it is delayed onset/reduced mechanical and thermal painrelated
likely that their algogenic effects, like those of mast cells, may hypersensitivity (Myers et al 1996, Ramer et al 1997). Sys-
partly be due to the subsequent recruitment and activation of temic depletion of macrophages also reduced both thermal
other immune cells such as macrophages. and mechanical hyperalgesia in the PSNL model of neuro-
pathic pain (Liu et al 2000, Barclay et al 2007).
Another means of inhibiting the pro-algesic actions of mac-
rophages is to reduce their recruitment from the circulation
Macrophages are leukocytes and represent a heterogeneous to the injured nerve. An important molecule for macrophage
group of cells resident in the majority of tissues. They are con- chemotaxis is CCL3, blockade of which reduces macrophage
tinually being replenished from a circulating peripheral blood inltration, as well as thermal and mechanical painrelated
mononuclear cell population, which itself originates from bone hypersensitivity (Kiguchi et al 2010). The toll-like recep-
marrow. These cells have homeostatic actions in their tissue of tors (TLRs) are pattern recognition receptors that respond
residence, such as clearing cell debris, as well as repairing and to structural motifs on pathogens and the products of tissue
remodeling tissue following damage and inammation. Mac- injury. They have an important role in macrophage recruit-
rophages derive from monocytes, which also generate a range ment and activation. Mice lacking TLR2 demonstrate absent
of other specialized cells contributing to innate immunity, macrophage recruitment and reduced neuropathic painlike
including microglia in the CNS, alveolar macrophages in the behavior (Shi et al 2011).
lung, Langerhans cells in the skin, osteoclasts in bone, Kupffer Another option for modulating the functional properties of
cells in the liver, and histocytes in connective tissue, as well these cells is to alter their functional status and thereby reduce the
as resident cells in the spleen, gastrointestinal tract, and the production of pro-inammatory cytokines (Kiguchi et al 2010).
peritoneum (Gordon and Taylor 2005). Following tissue dam- This can be achieved by treatment with anti-inammatory cyto-
age or infection, the macrophage population is augmented by kines such as IL-10 (Wagner et al 1998). Trying to change the
blood-derived monocytes. The resident as well as the inltrat- phenotype of macrophages from a pro- to an anti-inammatory
ing macrophages react to endogenous danger signals released state may be a better therapeutic option than trying to globally
by necrotic cells or exogenous signals such as factors pro- inhibit their recruitment to or function within the injured nerve
duced by microorganisms and appropriately release cytokines because they are essential for effective nerve repair (Barrette
to orchestrate the innate and adaptive immune response. A et al 2008).
strong body of evidence suggests a role of macrophages in the
development of both inammatory and neuropathic pain. Dendritic Cells
Intraperitoneal injection of acetic acid or zymosan is used as
a model of visceral pain and induces overt pain-like behavior Dendritic cells (DCs) are closely related to macrophages; they
in rodents in the form of a writhing response. This behavior are primarily antigen-presenting cells but also have phagocytic
can be exacerbated by increasing the macrophage population capabilities and can release cytokines and chemokines. Some
(Ribeiro et al 2000). Inhibiting the production of inamma- of the pro-nociceptive effects of IL-17 may be mediated by
tory mediators by macrophages through treatment with either these cells (Ruts et al 2010, Kim and Moalem-Taylor 2011b).
anti-inammatory cytokines or pentoxifylline (which reduces In the epidermis these cells are referred to as Langerhans cells
activation of these cells via a poorly dened mechanism) has (LCs). Following traumatic nerve injury, epidermal nerve
been shown to reduce inammatory pain (Vale et al 2003, ber density is decreased. However, spared bers that inter-
2004). Mice decient in the purinergic receptor P2X4 dem- mingle with degenerating axons share innervation territories,
onstrate reduced mechanical hyperalgesia following either and these spared axons have an important role in the genera-
CFA or carrageenan application. This effect is attributed to tion of neuropathic pain. The endings of these spared axons
a reduction in the release of PGE2 from tissue-resident mac- show increased association with LCs after nerve injury (Lin
rophages, which would normally occur in a P2X4-dependent et al 2001, Lindenlaub and Sommer 2002). In chemotherapy-
manner, and in agreement, injection of ATP-stimulated mac- induced neuropathic painlike states these LCs express OX-6,
rophages from wild-type mice into P2X4-decient mice was a marker of activation associated with pro-inammatory cyto-
able to induce mechanical hyperalgesia (Ulmann et al 2010). kine production (Siau et al 2006). This same phenomenon has

been seen in skin biopsy samples taken from patients with pain (Tsai and Won 2001), and although their numbers do
complex regional pain syndrome (Calder et al 1998), and in increase in some nerve injuries, this is not associated with the
diabetic patients with small-ber neuropathy, the number of development of hyperalgesia (Cui et al 2000). B lymphocytes
LCs is increased in the skin in comparison to control samples mediate the humoral arm of the adaptive immune response
(Casanova-Molla et al 2012). DCs also inltrate the injured and produce specic antibodies against presented antigens.
sciatic nerve distal to and at the site of injury. This inltration A recent study looking at immune cell inltration into the sci-
is delayed and occurs 1 week after the initial injury when a atic nerve found a signicant increase in the number of B cells
robust thermal and mechanical painrelated hypersensitivity 314 days after injury, particularly at the site of damage (Kim
takes place (Kim and Moalem-Taylor 2011a). Although these and Moalem-Taylo, 2011a). However, there does not seem to
cells respond to a number of different types of tissue injury, be any direct evidence linking B cells to the development or
there is as yet no direct evidence that they contribute to per- maintenance of persistent pain. In fact, full neuropathic pain
sistent pain states. like behavior develops in B celldecient mice following nerve
injury (Costigan et al 2009). Eosinophils and basophils are,
like neutrophils, PMN cells that play a role in both parasitic
T Cells
infection and the bodys response to allergens. There is little
T cells are lymphocytes activated by the presentation of anti- evidence linking these cells to pain modulation. Both these
gens. They mediate cellular immunity either by directing cell types can release a variety of pro-algesic factors, and fur-
the immune response via the release of cytokines to activate ther study is required to elucidate any possible role in pain
innate immune cells or through the destruction of infected pathophysiology.
cells. More than most, T cells represent a heterologous group
of immune cells loosely divided into CD4+ (helper) and CD8+ Production of Immune Mediators
(cytotoxic) with type 1 and type 2 subsets. Th1 cells release
by Non-immune Cells
pro-inammatory cytokines that activate neutrophils, mac-
rophages, and natural killer (NK) cells, whereas Th2 cells Many immune cells in their quiescent state do not appear to
release anti-inammatory cytokines that activate humoral interact with nociceptive systems. However, following tissue
immunity and strongly deactivate macrophages (OGarra and injury some cells undergo a profound phenotypic change that
Arai 2000). results in the release of cytokines and chemokines. These fac-
T cells have a pivotal role in autoimmune diseases. RA rep- tors can recruit more immune cells and may also act as pain
resents one such disease that is commonly associated with per- mediators. Non-immune cells can play an important role in
sistent pain, T-cell inltration, and cytokine production (Toh initiating this process. An example is keratinocytes found
and Miossec 2007). Abatacept is a fusion protein that pre- within the epidermis, an important innervation target in
vents the activation of T cells and decreases pain in patients which the naked endings of nociceptors terminate. Following
with RA. In models of neuropathic pain induced by either CCI injury or disease, keratinocytes can release an array of cyto-
or PSNL, the number of T cells is signicantly increased in kines, chemokines, and growth factors (Pastore et al 2006,
the injured nerve in comparison to controls (Cui et al 2000, Li et al 2011), which can have sensitizing actions on noci-
Kim and Moalem-Taylor 2011a). This increase is associated ceptors, as well as endogenous opioids, which can have an
with both thermal and mechanical painrelated hypersensitiv- analgesic action (Khodorova et al 2003). A further example
ity (Cui et al., 2000). Neuropathic painrelated behavior is is Schwann cells, which in normal nerves are intimately asso-
reduced in T celldecient mice or in mice that lack the ability ciated with axons: myelinating Schwann cells wrap around
to produce mature T cells (Moalem et al 2004, Kleinschnitz peripheral axons to form the myelin sheaths that facilitate
et al 2006, Cao and Deleo 2008, Costigan et al 2009). Passive axonal conduction. There are also non-myelinating Schwann
transfer of Th1 cells into mature T celldecient mice is able cells, which in nerve bers ensheathe small-diameter unmy-
to restore full neuropathic painlike behavior, and this pain elinated axons, usually in groups called Remak bundles
behavior can be attenuated by Th2 cells in immune-competent (Grifn and Thompson 2008). In the process of wallerian
mice (Moalem et al 2004). Guillain-Barr syndrome is an degeneration these cells de-differentiate and proliferate.
autoimmune disorder affecting the peripheral nervous system. They produce a variety of pro-algesic factors such as NGF
The syndrome is a form of peripheral neuropathy and is com- (Bandtlow et al 1987, Heumann et al 1987, Matsuoka et al
monly associated with abnormal pain (Ruts et al 2010). Rats 1991); cytokines such as TNF-, IL-1, and IL-6 (Bolin et al
with experimental autoimmune neuritis model this syndrome, 1995, Shamash et al 2002, Wagner and Myers 1996); and
and these animals display robust neuropathic painlike behav- chemokines such as CCL2 (Fu et al 2010). Such factors may
ior and signicant expression of T cells in the affected nerves act directly by sensitizing the remaining intact axons within
(Moalem-Taylor et al 2007, Ruts et al 2010). injured nerves (Sorkin et al 1997) and may also have a role
in the recruitment of immune cells (Tofaris et al 2002, Per-
rin et al 2005), thereby contributing to the development of
Other Immune Cells
neuropathic pain.
Many other cells have immune functions and orchestrate Clearly, then, there is a large body of evidence showing
both innate and adaptive immunity. NK cells are lympho- that immune cells are important contributors to the develop-
cytes and constitute up to 20% of the mononuclear cells ment of multiple types of persistent pain. Immunosuppressive
found in the blood and spleen. They target and kill infected or strategies, however, are in general not useful in treating pain
stressed cells, thereby playing a major role in tumor rejec- because, of course, many aspects of inammation are of use in
tion, and can release many pro-inammatory cytokines. NK promoting tissue repair. A more productive strategy is likely
cell activity is not altered in the CCI model of neuropathic to be the identication of mediators produced by immune
60 Section One | Neurobiology of Pain

cells that lead to activation and sensitization of nociceptors. et al 1992), which may allow generalized sensitization of sen-
Below we consider the evidence for such specic mediators. sory neurons in the absence of functional TNF- receptors.
In addition to these direct actions on sensory neurons, it is
clear that a large proportion of the algogenic effect of TNF-
IMMUNE CELL AND NEUROTROPHIC and IL-1 is mediated via NGF. Neutralizing antisera or
FACTORS AS PAIN MEDIATORS other molecules blocking NGF prevent the pain produced by
AND MODULATORS these inammatory cytokines. Mast cells also express trkA
(Horigome et al 1993) and in response to NGF proliferate,
degranulate, and release inammatory mediators, including
One well-recognized consequence of inammation is the pro- TNF- (Woolf et al 1996). Because mast cells also release
duction of various prostanoids, but the limited efcacy of NGF, there is the possibility of a vicious circle of events pro-
NSAIDs that target COX enzymesand therefore prostanoid moting pain.
productionstrongly suggests a role for other inamma- Leukemia inhibitory factor (LIF) and IL-6 both belong to
tory mediators. The inammatory process, triggered by the a family of neuropoietic cytokines dened by their binding to
recruitment of immunocompetent cells and the generation of the common receptor gp130. Other members include IL-11,
free radicals, leads to the release of several other algogenic ciliary-derived neurotrophic factor, oncostatin M, and car-
mediators. NGF is one such mediator, and the biology of this diotrophin-1. LIF signals via a receptor complex of the LIF
factor is discussed at some length below since anti-NGF thera- receptor- and gp130 and is retrogradely transported by a
pies are now being tested in the clinic. TNF- and IL-1 are population of small-diameter DRG cells (Thompson et al
two inammatory cytokines that also contribute to inamma- 1997). Levels of LIF are normally very low. However, fol-
tory pain. Administration of small doses of TNF- or IL-1 to lowing nerve injury, LIF expression increases at the site of
adult animals and humans can produce pain and hyperalgesia injury (Banner and Patterson 1994). Nerve injury also results
that start within minutes in some cases and typically persist in a large increase in expression of the neuropeptide galanin
for several hours (see Watkins and Maier 2003, McMahon within sensory neurons. Evidence from both animals decient
and Cafferty 2004, Sommer and Kress 2004). Both these fac- in LIF (Sun and Zigmond 1996) and the administration of
tors are capable of activating and sensitizing peripheral noci- exogenous LIF (Thompson et al 1998) indicates that this cyto-
ceptive neurons and thereby contribute to ongoing pain and kine is responsible for up-regulation of galanin. LIF may also
hyperalgesia. There is evidence demonstrating that neutral- be implicated in the sprouting of post-ganglionic sympathetic
ization or block of IL-1 and TNF- is also effective in pre- neurons that occurs around DRG cell bodies following nerve
venting abnormal pain behavior in some inammatory pain injury (Thompson and Majithia 1998).
models (see Sommer and Kress 2004). Antibodies against The actions of LIF are not restricted to nerve injury but
TNF- and IL-1 are now in clinical use for the treatment of also extend to inammatory conditions (Banner et al 1998).
inammatory arthritis and are proving very successful both in LIF levels increase during inammation. LIF knockout mice
treating disease symptoms, including pain, and in modifying have an enhanced inammatory reaction. Conversely, admin-
the course of the disease (Fleischmann et al 2004, Iannone istration of exogenous LIF can attenuate both the hyperal-
et al 2007, Laas et al 2009). The analgesic effects of block- gesia and the increased NGF expression that normally occur
ing TNF- are also seen in patients with osteoarthritis (OA) during inammation. Confusingly, the effects of exogenous
of the hand, for which they have been shown to signicantly LIF may be dose dependent in that another study has found
reduce spontaneous as well as pressure-evoked pain (Fiora- that administration of this factor to nave animals may itself
vanti et al 2009). produce hyperalgesia (Thompson et al 1996). Endogenous
Sensory neurons are known to express receptor components LIF, however, appears to have an interesting role as a media-
capable of transducing extracellular TNF- (Pollock et al tor that suppresses the inammatory reaction possibly at an
2002) and IL-1 (Gardiner et al 2002). Intraneural injection of early stage by negatively regulating the expression of IL-1
either TNF- or IL-1 can induce both thermal and mechani- and NGF.
cal hyperalgesia (Zelenka et al 2005), and blocking either of IL-6 can exert its biological effect through the binding of
these factors peripherally following nerve injury attenuates either a membrane-bound IL-6 receptor or a soluble receptor
such pain behavior (Lindenlaub et al 2000, Schafers et al subunit, both of which need to form a complex with gp130
2003, Kiguchi et al 2010). For TNF- these effects seem to be for signal transduction. Sensory neurons, which constitutively
mediated via TNFR1 and not TNFR2 (Sommer et al 1998). In express gp130 (Gardiner et al 2002), lack the IL-6 membrane
addition, intraplantar injection of TNF- (Cunha et al 1992, receptor, and it is therefore likely that direct actions of IL-6
Perkins et al 1994) or IL-1 (Saeh-Garabedian et al 1995, on these cells involve it and the soluble form of the receptor
Amaya et al 2006) can induce hypersensitivity to both thermal binding to a cell. Intraplantar injection of IL-6 induces a dose-
and mechanical stimuli. These effects can be mediated directly dependent mechanical hyperalgesia (Cunha et al 1992). Mice
on nociceptors; both TNF- and IL-1 have been shown to decient in IL-6 show both reduced thermal and mechanical
increase the excitability of nociceptive neurons by enhancing hyperalgesia following inammation or nerve injury (Xu XJ
TTX-resistant sodium channel currents via the activation of et al 1997, Ramer et al 1998). By measuring release of CGRP,
intracellular cascades involving p38 MAPK (Jin and Gereau it seems that IL-6, in combination with its soluble recep-
2006, Binshtok et al 2008). TNF- can also enhance the sen- tor, can sensitize nociceptors in the skin to thermal stimuli
sitivity of TRPV1 to contribute to thermal hypersensitivity (Obreja et al 2002), and electrophysiological experiments
(Nicol et al 1997, Jin and Gereau 2006). Intriguingly, trimers have also reported that this cytokine can sensitize joint affer-
of TNF- have been reported to insert into membranes and ents to mechanical stimulation (Brenn et al 2007). The effect
form functional voltage-dependent sodium channels (Kagan of IL-6 on pain behavior could be direct since IL-6 can elicit

calcium transients in around 33% of DRG neurons in vitro Table 3-2 Chemokines as Peripheral Pain Mediators
(von Banchet et al 2005). This evidence is suggestive of a role GENE NAME FC IN RAT FC IN HUMAN
of IL-6 as a peripheral pain mediator, and this notion has
been highlighted recently by a study using an antigen-induced CXCL5 51.3 (20.5128.2)* 82.5 (45.4150.0)*
arthritis model. Here, local neutralization of the IL-6/soluble iNOS 34.3 (3.1385.1) 1.1 (2.21.8)
IL-6 receptor complex with soluble gp130 in the knee joint IL-24 32.7 (8.3128.8)* 63.7 (44.591.3)*
signicantly attenuated mechanical hyperalgesia to a greater
CXCL2 24.6 (3.1198.4)* 12.0 (8.018.0)*
extent than did repeated systemic delivery (Boetteger et al
2010). Like IL-1 and TNF-, therapies that block IL-6 are CCL4 15.4 (6.635.8)* 2.5 (1.44.5)
used clinically and have been shown to reduce pain scores in IL-6 14.8 (4.153.9)* 54.7 (30.399.0)*
RA patients (Smolen et al 2008, Burmester et al 2011). CCL2 14.6 (5.340.6)* 5.1 (3.87.0)*
These same immune-related factors and others can also act
CCL7 14.2 (6.232.6)* 13.8 (4.244.8)*
as pain mediators in the CNS, and such actions are discussed
in Chapter 4. CXCL7 14.0 (2.870.5) 4.0 (1.88.6)
CCL11 11.6 (5.922.9)* 4.2 (1.116.6)
Chemokines IL-10 10.7 (5.421.2)* 8.0 (4.1158)*

Chemokines are chemotactic cytokines and have a key role IL-3 9.0 (3.423.3) ND
in immune cell recruitment. They are small molecules (810 G-CSF 7.1 (1.262.2) 25.0 (10.758.5)*
kDa) and are structurally related with four conserved cysteine IL-19 6.2 (3.012.6) ND
residues. They signal via GPCRs, and a level of complexity is
CCL3 6.0 (2.918.9) 16.6 (10.725.7)*
added by the fact that multiple chemokines may signal via one
receptor. Like a number of cytokines, there is good preclini- CXCL4 6.0 (3.99.2)* 2.1 (1.15.0)
cal evidence to suggest that some chemokines, particularly KGF 5.8 (3.210.5)* 4.3 (2.96.5)*
CCL2 and CX3CL1, are able to modulate pain processing at CXCL1 5.4 (1.915.5) 18.9 (12.628.4)*
the level of the spinal cord. However, there is also evidence
IL-1 5.0 (1.318.7) 10.3 (5.917.8)*
suggesting that this family of chemotactic cytokines can act
as peripheral pain mediators. For example, inammation or COX-2 4.6 (2.010.6) 5.3 (3.09.5)*
tissue injury can up-regulate numerous chemokine ligands, Numerous chemokines can be up-regulated by tissue injury or inammation, and
and the application of such factors can induce pain-related one such example is ultraviolet B (UVB) irradiation. In both human and rat skin the
transcriptional expression of various chemokines is increased at the peak of UVB-
behavior (as highlighted in Table 3-2 and in Fig. 3-2A). These induced hyperalgesia when compared with control skin.
actions can be achieved either through direct actions on noci- *P < 0.001.
P < 0.05.
ceptive neurons or through the recruitment of immune cells P < 0.01; mean FC (1 SD range).
(as shown in Fig. 3-2B) and the subsequent release of other From Dawes JM, Calvo M, Perkins JR, et al 2011 CXCL5 mediates UVB
algogenic factors. irradiationinduced pain. Science Translational Medicine 3(90):90ra60, Table 1.
A number of chemokines have been shown to modulate
peripheral pain pathways. This was rst shown with the
intraplantar injection of exogenous human CXCL8, also to recapitulate neuropathic painlike behavior when given
known as IL-8, which induced dose-dependent mechanical intraneurally (Kiguchi et al 2010). One possible mechanism
hyperalgesia in rats (Cunha et al 1991). Interestingly, there by which chemokines may inuence the perception of noci-
is no direct rodent ortholog of this chemokine, but CXCL1 ceptive input is via direct interaction with sensory afferents.
seems to elicit similar effects when given to nave rats, and A number of chemokines can directly act on DRG neurons,
antiserum against it attenuates carrageenan-induced mechani- as seen with calcium imaging (Oh et al 2001). These same
cal hyperalgesia (Lorenzetti et al 2002, Qin et al 2005). In chemokines were also able to induce pain-related behavior
terms of the inuence that chemokines have in persistent when injected into the paw. Subsequent to this work it was
pain states, the majority of work suggests a prominent role shown that CCL3 was capable of sensitizing TRPV1 on DRG
for the CCL2/CCR2 axis. CCL2 is up-regulated in periph- neurons and that sodium currents in cultured sensory neurons
eral tissues in neuropathic (Perrin et al 2005, Fu et al 2010) could be enhanced by incubation with CXCL1 (Wang et al
and inammatory pain states such as intraplantar CFA injec- 2008). In addition, CCL3 might also be able to desensitize
tion (Jeon et al 2008). Indeed, up-regulation in a number of opioid receptors on sensory neurons, thereby preventing the
different pain models was recently emphasized in a meta- analgesic effects of endogenous opioids released following
analysis of micro-array studies (LaCroix-Fralish et al 2011). tissue injury (Zhang et al 2004). The idea that chemokines
When injected into the paw, CCL2 is able to elicit both ther- can act directly on sensory neurons requires that appropri-
mal and mechanical hyperalgesia (Abbadie et al 2003, Qin ate receptors be expressed by these cells. Following nerve
et al 2005, Bogen et al 2009). In addition to these ndings, injury the chemokine receptors CCR2, CCR5, and CXCR4
ablation of CCR2, the predominant receptor for CCL2, pre- can be expressed by DRG neurons, and cells in this condition
vents the development of mechanical hyperalgesia following have been shown to increase their responsiveness to a num-
nerve injury (Abbadie et al 2003). CCL2 therefore acts as a ber of chemokine ligands, including CCL2, CCL5, CXCL10,
peripheral pain mediator in the setting of nerve injury and/or and CXCL12 (White et al 2005; Sun et al 2006; Bhangoo
inammation. Another closely related chemokine, CCL3, can et al 2007, 2009; Jung et al 2008). One study using in vivo
produce pain-related hypersensitivity when applied peripher- electrophysiological techniques showed that after a chronic
ally (Zhang et al 2005a, Eijkelkamp et al 2010) and is able compression injury of the spinal nerve, DRG neurons were
62 Section One | Neurobiology of Pain

to attenuate the mechanical hyperalgesia induced by periph-
16 0.1 g CXCL5 eral injection of carrageenan, zymosan, LPS, and CFA and
1 g CXCL5 that caused by nerve injury (Cunha et al 2008a, Manjava-
50% withdrawal threshold (g)

3 g CXCL5 chi et al 2010). These analgesic effects are associated with
12 reduced neutrophil inltration. The ultraviolet B (UVB)
10 model of inammatory pain is associated with both neutro-
phil and macrophage inltration and up-regulation of numer-
ous chemokines at the peak of both thermal and mechanical
6 hyperalgesia (Dawes et al 2011). Neutralization of one of the
4 most overexpressed chemokines, CXCL5, which also acts via
* the CXCR2 receptor, was able to reduce the UVB-induced
2 mechanical hyperalgesia and inltration of immune cells. In
0 addition, the pro-algesic properties of this chemokine in nave
BL 0.5 3 6 24 animals involved the recruitment of both neutrophils and
Time after chemokine injection (hr)
macrophages (Dawes et al 2011).
A number of chemokines are up-regulated in injured
peripheral nerves. One of these, CCL2, is particularly pivotal
in the recruitment of macrophages (Toews et al 1998)cells
B that seem crucial for the full development of neuropathic pain
(see the previous section on immune cells; Liu et al 2000, Bar-
clay et al 2007). With the use of bi-transgenic reporter mice
in a focal demyelination model of neuropathic pain it has
been suggested that a large proportion of the pro-nociceptive
effects of CCL2 occur in peripheral nerves because of its
action on CCR2-expressing leukocytes (Jung et al 2009). In
this same model, disruption of this interaction with a CCR2
Figure 3-2. Chemokines as peripheral pain mediators. A, When injected antagonist signicantly attenuates neuropathic painlike
into nave rats, the chemokine, CXCL5, was able to recapitulate ultraviolet behavior (Bhangoo et al 2007). CCL3 is also up-regulated in
Binduced mechanical hypersensitivity. B, In addition, the increase in mechani- injured nerves (Perrin et al 2005, Kiguchi et al 2010). Local
cal sensitivity was associated with the inltration of numerous neutrophils and neutralization of CCL3 was able to attenuate both thermal
macrophages into the chemokine-treated skin. (From Dawes JM, Calvo M,
Perkins JR, et al 2011 CXCL5 mediates UVB irradiationinduced pain. Sci- and mechanical hyperalgesia following nerve damage, and
ence Translational Medicine 3(90):90ra60, Fig. 3AC.) this was associated with a reduction in the level of macro-
phages (Kiuchi et al 2010).

depolarized by CCL2 and lowered their threshold for activa- Resolution of Inammation
tion with this ligand (Sun et al 2006). Although this effect was
clear in DRG neurons from injured animals, some responses The inammatory cascade is under complex regulatory
were also measured in neurons from uninjured ganglia (Sun control, and regulatory factors include anti-inammatory
et al 2006). Via an immunohistochemical approach in nave cytokines (IL-4, IL-10, IL-13, transforming growth factor
rats, expression of both CCR1 and CXCR2 has been found [TGF-]), promoters of resolution (lipoxins, neuroprotectins,
in a high proportion of sensory neurons from nave animals maresins, resolvins), endocannabinoids, and inhibitors of pro-
(Zhang et al 2005a, Wang et al 2008). In addition, Oh and inammatory signaling pathways (inhibitor of the nuclear
colleagues (2001) detected mRNA for CXCR4, CX3CR1, factor NF-B, complement inhibitors, IL-1R antagonist,
CCR4, and CCR5 in DRGs, as well as staining for CXCR4 co-stimulatory molecules, and MAPK phosphatases). These
and CCR4 in vitro. Therefore, a range of chemokines released systems may be exploited to terminate inammation, and a
by either resident or inltrating cells into damaged tissue number of these mediators have been shown to have analgesic
could act directly on nociceptor nerve terminals to enhance actions. An example is the resolvins, which are endogenous
pain perception. lipid mediators derived from -3 fatty acids. These factors
Chemokines may also act indirectly to induce pain-related promote resolution of inammation through inhibition of leu-
hypersensitivity. For example, the pro-algesic actions of both kocyte recruitment and can directly modulate sensory trans-
CXCL8 and CXCL1 have been attributed to their ability to duction and synaptic plasticity within the dorsal horn (Serhan
induce the release of sympathetic amines from resident cells et al 2002, Xu et al 2010, Park et al 2011). They have been
(Cunha et al 1991, 1992, 2005; Ben-Baruch et al 1995; Loren- shown to have potent analgesic actions in inammatory pain
zetti et al 2002), which can act to directly sensitize nocicep- states (Xu et al 2010, Park et al 2011).
tors. The majority of these indirect effects, however, are most
likely to involve the recruitment of immune cells, cells that are Neurotrophic Factors
known to inltrate areas of damaged tissue. CXCL1-induced
hyperalgesia is associated with neutrophil recruitment into In 1996 a study was published on the genetic basis of the con-
the treated peripheral tissue (Cunha et al 2008a, 2008b). genital insensitivity to pain observed in a single family (Indo
This chemokine attracts neutrophils predominantly through et al 1996). A mutation was identied in the gene encoding
activation of the CXCR2 receptor. Systemic treatment with a a tyrosine kinase receptor known as trkA. This protein is the
CXCR1/2 inhibitor or specic antagonism of CXCR2 is able high-afnity receptor for a single trophic factor, NGF, and the

mutation disrupts the normal signaling of NGF. This single NGF receptor trkA (Verge et al 1989, 1992; McMahon et al
example provides a startling example of the importance of 1994; Averill et al 1995; Kashiba et al 1995; Molliver et al
trophic factors in general and NGF in particular for normal 1995; Wetmore and Olson 1995), and cells that express trkA
nociceptive functioning. Several clinical trials have indicated are principally of small cell diameter. TrkA is expressed prin-
the analgesic efcacy of blocking NGF, and we now have a cipally in the peptidergic population of small-diameter DRG
good understanding of the mechanisms by which NGF inter- cells, whereas very few non-peptidergic (isolectin B4-binding)
acts with pain-signaling systems, which we review here. small-diameter DRG cells express trkA (Averill et al 1995,
Neurotrophic factors can be dened as factors that regu- Molliver et al 1995). Some of the myelinated DRG cells
late the long-term survival, growth, or differentiated function (i.e., those that express neurolament 200) do express trkA
of discrete populations of nerve cells. There are many neuro- (around 20%). TrkA-immunoreactive terminals within the
trophic factors, and multiple factors can affect a single popu- spinal cord are present within laminae I and IIouter. TrkA is
lation of neurons. However, trophic factors fall into a smaller therefore expressed in small-diameter DRG cells that express
number of families, with members being related by high levels CGRP and project to the supercial laminae of the spinal
of structural homology or by the common or related recep- cord. These are all characteristic of nociceptive afferents.
tors that they use in exerting biological actions. The num- Thus, about half of the nociceptors in adult animals express
ber of factors identied as affecting sensory processing is both p75 and trkA and are therefore likely to be sensitive to
limited. Most data relate to just two families of factors: the NGF. The other half of the nociceptor population does not
neurotrophin family and the GDNF-related family. Here we express any trk receptor, nor p75. Rather, they express recep-
primarily consider one member of the neurotrophin family tors for members of the GDNF family of receptors. Interest-
NGF. Other members of the neurotrophin family are BDNF, ingly, these two populations of C bers have different central
neurotrophin-3, and neurotrophin-4/5 (Gotz et al 1994, Lind- terminations, even though it is not yet clear whether they
say 1996). In general, these members share around 50% of have distinct functional roles (although the receptors that
their amino acid sequence. At physiological concentrations, they express do indicate that they can be activated by differ-
the neurotrophins exist as homodimers. The neurotrophins ent putative pain mediators).
are initially expressed as pre-pro-precursors, which when During development it appears that functionally distinct
processed, yield highly basic mature proteins of around 13 groups of sensory neurons depend on different neurotrophins
kDa (120 amino acids). These pre-pro-precursors themselves for survival. Animals with a gene deletion of either NGF or
might be biologically active, and currently there is much dis- trkA are born with DRGs lacking virtually all small-diameter
cussion whether some of the pro-forms of neurotrophins are primary sensory neurons, including the peptidergic neurons
secreted and act on specic receptors (Teng et al 2010). Bind- expressing CGRP and substance P (Crowley et al 1994).
ing studies have demonstrated the presence of both high- and These animals are, as expected, profoundly hypo-algesic. In
low-afnity binding sites for NGF on responsive cell lines utero deprivation of NGF, achieved by antibody treatment,
(Bothwell 1995). Two different classes of neurotrophin recep- produces similar effects (Johnson et al 1980, Ruit et al 1992),
tor have now been characterized (for reviews see Barbacid and this phenotype is equivalent to that seen in patients with
1995, Chao and Hempstead 1995). The rst to be cloned loss-of-function mutations in trkA, which also leads to loss of
was the p75 or low-afnity NGF receptor LNGFR, which peripheral pain-signaling neurons.
binds all the neurotrophins more or less equally with rela- The developmental dependence of nociceptors on NGF for
tively low afnity (Chao et al 1986). Additionally, there is a survival is lost in the postnatal period, some time before the
family of high-afnity receptors, trks, that are tyrosine kinase second week of life in the rat and presumably in the rst few
receptors (Kaplan et al 1991). The p75 receptor is thought years of life in humans. However, NGF continues to exert
to play several roles and may serve as the preferred receptor profound effects on adult nociceptors. Adult DRG neurons
for pro-NGF. It can also interact with the trk receptors and can be cultured in the absence of added trophic factors (Lind-
modulate the specicity and sensitivity of neurotrophin inter- say 1988). If NGF is then added to these cultures, extensive
action. There are three known members of the trk family of neurite outgrowth of trkA-positive cells is promoted. NGF in
receptors, trkA, trkB, and trkC, and all show different speci- these cultures also regulates expression of the neuropeptides
cities for the neurotrophins. NGF is the preferred ligand for substance P and CGRP (Lindsay and Harmar 1989). In addi-
trkA, BDNF and neurotrophin-4/5 are the preferred ligands tion, NGF regulates the chemical sensitivity of cultured sen-
for trkB, and neurotrophin-3 is the preferred ligand for trkC sory neurons. For example, the sensitivity of cultured sensory
(Ip et al 1993). neurons to the potent algogen capsaicin is increased by NGF,
A great deal of the information about signal transduction as is their sensitivity to protons and to -aminobutyric acid
following trk activation comes from the study of events fol- (GABA) (Winter et al 1988, Bevan and Winter 1995). Expres-
lowing activation of trk by NGF in PC12 cells. After NGF sion of bradykinin binding sites in cultured sensory neurons
binding, receptor dimerization occurs, which is critical for has also been shown to be regulated by NGF (Petersen et al
receptor activation (Clary et al 1994). The tyrosine kinase 1998), apparently in a p75 receptordependent manner. This
domain of the receptor is activated and a number of substrates marked regulation of the chemosensitivity of cultured sensory
are phosphorylated; autophosphorylation of the receptor also neurons by NGF is interesting in relation to the association
occurs. There is now a large body of evidence demonstrating between NGF and inammatory pain, and the in vivo effects
that neurotrophin receptors are expressed in specic popula- of NGF are discussed here.
tions of DRG cells. With double-labeling techniques it has The effects of NGF extend from the peripheral to the cen-
been possible to relate receptor expression to different func- tral terminals of sensory neurons, and many are mediated via
tional classes of DRG cells. Multiple approaches have dem- altered gene expression in neurons expressing trkA. These
onstrated that approximately 40% of DRG cells express the effects are summarized in Figure 3-3.
64 Section One | Neurobiology of Pain

Substance P
Na2+ channels
Sensitization Bradykinin receptors
Mast cell degranulation Central sensitization
Sympathetic baskets
Neutrophil accumulation Substance P
Figure 3-3. Summary of the biological
effects of exogenous nerve growth factor
B (NGF) on pain-signaling systems in normal
animals (A) and in animals with nerve injury
(B). In normal animals, NGF causes periph-
eral sensitization of some nociceptors, in part
directly as a result of NGF binding to recep-
tors on nociceptors and in part indirectly by the
release of algogens from other cell types. NGF
also regulates the expression of many genes in
Reverse substance P trkA-expressing neurons, ranging from trans-
Reverse CGRP mitters and modulators to ion channels and
Reverse trk A receptors. In the spinal cord, NGF produces
central sensitization via altered expression of
putative neuromodulators, particularly brain-
Reverse conduction velocity derived neurotrophic factor (BDNF). CGRP,
calcitonin generelated peptide; TRPV1, tran-
sient receptor potential vanilloid 1.

Administration of small doses of NGF to adult animals they follow activation of trkA on nociceptors), and some are
and humans can produce pain and hyperalgesia. In rodents, indirect and mediated by NGF inducing the release of other
thermal hyperalgesia is present within 30 minutes of sys- algogens from a variety of peripheral cell types. The direct
temic NGF administration and both thermal and mechani- mechanisms involve both altered gene expression and post-
cal hyperalgesia after a couple of hours (Lewin et al 1993). translational regulation of receptors and ion channels. There
Subcutaneous injections of NGF also produce both thermal are now multiple examples of post-translational changes
and mechanical hyperalgesia at the injection site. In humans, induced by NGF that involve phosphorylation of receptors
intravenous injections of very low doses of NGF produce and ion channels, although other actions are possible, such as
widespread aching pain in deep tissues and hyperalgesia at altered trafcking of receptors. The heat sensitization of noci-
the injection site (Petty et al 1994). Detailed quantitative ceptors induced by NGF is prominent and rapid. Phosphory-
sensory testing in human volunteers has demonstrated long- lation of particular residues on TRPV1 receptors appears to
lasting mechanical and thermal hypersensitivity following the account for most of the effect. However, the intracellular
intradermal injection of NGF (Rukweid et al 2010). The rapid cascades responsible are disputed, with published data sup-
onset of some of these effects and their localization to the porting a critical role for PKA, PKC, MAPK ERK1/2, or a
injection site strongly suggest that they arise, at least in part, mechanism involving inhibition of PIP2 (see Bonnington and
from a local effect on the peripheral terminals of nociceptors. McNaughton 2003). NGF has also been shown to enhance
This has been substantiated by the observation that acute mechanically activated currents in cultured sensory neurons
administration of NGF can sensitize nociceptive afferents (Di Castro et al 2006). The post-translational modication of
to thermal and chemical stimuli (Rueff and Mendell 1996). some ion channels, particularly TTX-resistant sodium chan-
Cutaneous nociceptors chronically exposed to elevated NGF nels, by NGF may likewise contribute to the sensitization of
levels (in an NGF-overexpressing mouse) show marked heat nociceptors by this agent (see Zhang et al 2002 and references
sensitization (Stucky et al 1998). Recordings of primary affer- therein).
ents innervating porcine skin following NGF application have Because cellular elements other than nociceptors in periph-
demonstrated reduced activity-dependent slowing in mechan- eral tissues express trkA, some of the sensitization of nocicep-
ically insensitive afferents and increased ongoing activity, thus tors by NGF may arise indirectly, and some of these elements
emphasizing the potential effects of NGF on axonal excitabil- have already been discussed. Mast cells contain a number of
ity (Obreja et al 2011). inammatory mediators known to excite primary afferents,
NGF produces sensitization of nociceptors by several including histamine and serotonin (Leon et al 1994), and some
mechanisms. Some of these mechanisms are direct (that is, types of mast cells express trkA receptors (Horigome et al

1994). NGF can produce mast cell degranulation (Mazurek for the responsiveness of nociceptors to noxious stimuli. NGF
et al 1986, Horigome et al 1994) and increase the prolifera- can also positively regulate the expression of other ligand-
tion of mast cells resident in tissue. In peritoneal mast cell cul- gated ion channels in nociceptors, including several ASICs
tures, NGF induces the expression of a number of cytokines (Mamet et al 2003) and the ATP receptor P2X3. In addition,
(Bullock and Johnson 1996). Mast cell degranulators and NGF may alter the excitability of sensory neurons by chang-
serotonin antagonists have both been demonstrated to par- ing the expression of several voltage-gated ion channels, for
tially prevent the thermal but not the mechanical hyperalgesia instance, the sodium channel Nav1.8 (Black and Waxman
(Lewin et al 1994, Woolf et al 1996) that occurs in response 1996, Boucher et al 2000). Because some forms of nocicep-
to NGF. These degranulators can signicantly reduce hyperal- tor sensitization appear to be mediated through this chan-
gesia (both thermal and mechanical) and the up-regulation of nel (Gold and Levine 1996), this provides another potential
NGF expression induced by CFA (Woolf et al 1996). mechanism by which NGF might regulate pain signaling.
In skin, NGF may also affect keratinocytes, some of which
express p75 receptors. NGF increases the proliferation of Actions on Spinal Processing of Nociceptive
keratinocytes in culture (Paus et al 1994, Fantini et al 1995), Information: Central Sensitization
and this process may contribute to tissue remodeling after NGF given systemically fails to penetrate into the spinal cord.
inammation. In addition, NGF may also target eosinophils There is also little trkA expression in the spinal cord, with the
and convert circulating eosinophils into tissue-type eosino- receptor largely being restricted to the terminals of primary
phils (Hamada et al 1996), and it has been reported to increase afferent nociceptors (Averill et al 1995). One might therefore
B- and T-cell proliferation (Otten et al 1989), thus suggesting imagine that exogenously administered NGF would have little
a role for NGF as an immunoregulatory factor. effect on spinal nociceptive processes. However, several of the
There may be an interaction between NGF and sympathetic biological effects of NGF described earlier are capable of lead-
neurons during inammation. Sympathetic efferents also pos- ing to secondary effects on the spinal cord. First, activation
sess the trkA receptor (Smeyne et al 1994). Surgical or chemi- and sensitization of primary afferent nociceptors may lead to
cal sympathectomy can reduce the short-latency thermal and sufcient afferent activity to trigger central changes. Second,
mechanical hyperalgesia evoked by NGF (Andreev et al 1995, the altered chemistry of afferent neurons produced by NGF
Woolf et al 1996). Production of eicosanoids by sympathetic may lead to increased neurotransmitter or neuromodulator
efferents within the skin has been suggested to contribute to release from nociceptive afferent terminals (Malcangio et al
hyperalgesia in some inammatory conditions (Levine et al 1997). Release of some sensory neuropeptides can contribute
1986b). However, a role for eicosanoids in NGF-induced to the induction of central sensitization. One might therefore
hyperalgesia is unlikely since it is unaffected by treatment expect that peripheral NGF treatment could lead to the induc-
with the NSAID indomethacin (Amann et al 1996). tion of central sensitization.
It has been shown that several hours after systemic NGF
Effects of NGF on Gene Expression and the treatment, C-ber stimulation produces greater than normal
Phenotypic Properties of Sensory Neurons amounts of central sensitization, seen as wind-up of ventral
Not all the algogenic and hyperalgesic effects of NGF can read- root reexes (Thompson et al 1995). A bers also develop the
ily be explained by peripheral processes. Some aspects of NGF novel ability to produce wind-up. Such changes in the cen-
actions are centrally mediated via altered gene expression in tral processing of nociceptive information may occur during
nociceptors. There appear to be a group of peptides that are inammation secondary to expression of substance P within
constitutively expressed in trkA cells and whose expression is A bers (Neumann et al 1996). There is considerable evidence
controlled mainly by NGF, with an increase following NGF that the ability of NGF to up-regulate BDNF expression in
supplementation and a decrease following NGF depletion some nociceptors may prove to be the most signicant mecha-
(resulting, for instance, from peripheral axotomy). CGRP nism by which NGF regulates the sensitivity of spinal process-
and substance P belong to this group (Goedert et al 1981, ing of noxious stimuli.
Otten et al 1984, Verge et al 1995). Based on NGFs ability to
reverse some axotomy-induced increases in peptide, it would Functional Role of NGF
appear that there is also a group of peptides whose produc- Because mice with NGF or trkA deletions rarely survive past
tion is partly inhibited by neurotrophins; vasoactive intestinal the rst postnatal week, most of what we know about endog-
peptide, cholecystokinin, neuropeptide Y, and galanin belong enous NGF function in the adult has been determined by
to this group. NGF also represses expression of the transcrip- the use of blocking agents. A number of studies have used
tion factor ATF3 (Averill et al 2004). In addition to an effect autoimmune models of NGF deprivation or infusions of NGF
on substance P and CGRP, NGF has been shown to produce a antisera to study the effects of NGF in normal adult animals.
dramatic up-regulation of BDNF mRNA and protein in trkA- Local infusion of trkAIgG (an NGF-neutralizing reagent;
expressing DRG cells (Apfel et al 1996, Michael et al 1997). Shelton et al 1995) into the rat hindpaw leads to thermal
This is interesting since there is good evidence to suggest that hypo-algesia and a decrease in CGRP content in DRG neu-
BDNF may serve as a central regulator of excitability (Pezet rons projecting to the infused area (McMahon et al 1995).
et al 2002, Coull et al 2005). These changes take several days to develop. In addition, there
NGF also regulates the expression of some of the receptors is a decrease in the thermal and chemical sensitivity of noci-
expressed by nociceptors. Capsaicin sensitivity is increased ceptors projecting to the area and a reduction in epidermal
in vivo by NGF. NGF-sensitive nociceptors (i.e., those innervation density (Bennett et al 1998a). These results pro-
expressing trkA) have the highest levels of TRPV1 (Tominaga vide strong evidence that NGF continues to play an important
et al 1998). Because TRPV1 is sensitive to heat and also to role in regulating the function of small, peptidergic sensory
protons, regulation by NGF is likely to have consequences neurons in the adult.
66 Section One | Neurobiology of Pain

By far the most extensively studied area of endogenous

NGF function in the adult is in models of relatively persis- A
tent inammatory pain (lasting at least several days). NGF is 120 Inflamed

Withdrawal time (exp/con) %

found in many cell types in tissues subjected to an inamma- Inflamed + trkAIgG
tory insult, and much evidence now supports the hypothesis 100
that up-regulation of NGF levels is a common component
of the inammatory response that relates to hyperalgesia. 90
Elevated NGF levels have been found in a variety of inam- 80
matory states in humans, including in the bladder of patients 70
with cystitis (Lowe et al 1997), and increased levels are pres-
ent in the synovial uid of patients with arthritis (Aloe et al
1992) and in the cerebrospinal uid of bromyalgia patients 50
(Sarchielli et al 2007). In animal studies, NGF is found in the 0 10 20 30 40 50 60
Time after carrageenan (hours)
exudate produced during blistering of the skin (Weskamp
and Otten 1987) and is elevated in skin after inammation
induced by CFA (Donnerer et al 1992, Woolf et al 1994),
IL-1 (Saeh-Garabedian et al 1995), ultraviolet light (Gil- 6
lardon et al 1995), or TNF- (Woolf et al 1997). Inflamed Inflamed

Neutral response

There is now widespread agreement that blocking NGF trkAIgG trkAIgG

can impede many of the effects of inammation on sensory 3
nerve function. For instance, intraplantar injection of carra-
geenan produces an acute inammatory reaction, which has
previously been widely used to study the analgesic effects of 1
NSAIDs. When the trkAIgG molecule was co-administered 0
with carrageenan, it could almost completely prevent devel- Skin temp. (C) 30 40 50
opment of the thermal hyperalgesia that normally occurs 50 Temperature (C)
(McMahon et al 1995; Fig. 3-4A). The properties of nocicep-
tive afferents innervating carrageenan-inamed skin have also 40
been studied. Following carrageenan inammation, there was
a marked increase in spontaneous activity in these afferents
and increased thermal and chemical sensitivity (Fig. 3-4B). 0 5 10 15 20 25
This probably represents the multiple peripheral actions of Time (sec)
NGF described earlier. Administration of the trkAIgG mol-
ecule could largely prevent these changes (Bennett et al 1996), Figure 3-4. The role of nerve growth factor (NGF) in inammation as
revealed by use of the NGF-sequestering protein trkAIgG. A, The ther-
and similar results have now been found in a number of dif- mal hyperalgesia that develops in rats in the hours following intraplantar
ferent inammatory models (see Pezet and McMahon 2006). carrageenan. The ordinate plots the ratio of the withdrawal times to radiant
The increased NGF levels observed after inammatory stim- noxious heat applied to the inamed paw and the non-inamed contralateral
uli result from increased synthesis and release of NGF from a paw. Most of the expected thermal hyperalgesia fails to develop in animals
inamed and concurrently treated with trkAIgG. B, Effects of carrageenan
variety of cell types, including keratinocytes, smooth muscle inammation on the properties of primary afferent nociceptors. Recordings
cells, and Schwann cell (Heumann et al 1987, Raychaudhuri were made from an isolated skinnerve preparation a few hours after the
et al 1998, Freund et al 2002). IL-1 and TNF- have been inammatory stimulus was given in vivo, and afferents were tested for their
shown to drive changes in NGF expression during inamma- responses to a ramp increase in skin temperature. In inamed skin, some
tion in vivo, and the hyperalgesia produced by these cytokines nociceptors develop spontaneous activity and show thermal sensitization.
In animals inamed with carrageenan and concurrently treated with trkA
can be prevented by NGF antagonism. IgG, the thermal sensitization of nociceptors is completely blocked. The inset
on the right shows the average stimulusresponse functions for nociceptors
Role of NGF in Clinical Pain States in these groups. (After McMahon SB, Bennett DL, Priestley JV, et al 1995
Findings from the sequestration of endogenous NGF and the The biological effects of endogenous nerve growth factor on adult sensory
neurons revealed by a trkA-IgG fusion molecule. Nature Medicine 1:774
administration of exogenous NGF suggest that this factor is 780; and Koltzenburg M, Bennett DL, Shelton DL, et al 1999 Neutraliza-
important in modulating the sensitivity of the sensory ner- tion of endogenous NGF prevents the sensitization of nociceptors supplying
vous system to noxious stimuli. The evidence that NGF levels inamed skin. European Journal of Neuroscience 11:16981704.)
increase during inammation, which is derived from studies
using NGF antagonism, makes a strong case for NGF being
a critical mediator of inammatory pain. NGF clearly has a humanized monoclonal antibody directed against NGF,
a powerful neuroprotective effect on small-diameter sensory given at 8-week intervals dose-dependently reduced the pain
neurons, and NGF levels have been shown to change in a associated with walking (Lane et al 2010). This effect lasted
number of models of nerve injury. The idea that NGF does for the whole study period and was maximal with the highest
act as a mediator in persistent pain states has recently been dose, which on average reduced pain scores by about 75%
tested in a series of clinical trials with encouraging results. (Fig. 3-5). The analgesic effects of blocking NGF are not lim-
The persistent pain associated with OA has a strong periph- ited to OA. Tanezumab also signicantly reduced pain scores
eral drive and represents an ideal platform to test whether in patients with lower back pain and pain arising from inam-
NGF may act as a peripheral pain mediator in this context. In mation of the bladder (Evans et al 2011, Katz et al 2011).
a 16-week study of patients with OA of the knee, tanezumab, In addition, in patients with lower back pain, tanezumab


doses of tanezumab induce a favorable side effect prole
(Schnitzer et al 2011). The block on NGF clinical trials was
Dose 1 Dose 2 lifted in early 2012, and it is likely that analgesic efcacy will
now be examined in multiple clinical trials.

Other Neurotrophic Factors

10 As Peripheral Pain Mediators
In addition to NGF, preclinical data also suggest that other
Change from baseline

20 neurotrophic factors can act as peripheral pain mediators. The

neurotrophins NT3 and BDNF both induce thermal hyper-
sensitivity in rats when injected into the hindpaw, and follow-
ing nerve injury, neutralization of BDNF in the periphery can
reduce the increase in thermal hypersensitivity (Theodosiou
40 et al 1999). In the adult system the non-peptidergic nocicep-
tive bers lack trkA but instead express c-Ret, the prominent
receptor for GDNF (Snider and McMahon 1998). When
injected into the paw of nave animals, GDNF is reported
to lower thermal painrelated thresholds (Malin et al 2006).
60 However, this factor might not act as a pro-algesic mediator
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 in persistent pain states since its application to nerve-injured
Week rats is analgesic (Boucher et al 2000). Artemin, a member of
the GDNF family of ligands, is also able elicit thermal hyper-
Mean change
from baseline
sensitivity when given intradermally. In inammation induced
over weeks 116 by CFA injection, artemin is greatly up-regulated at a tran-
Placebo 15.5 2.6 scriptional level in the skin in the rst 24 hours (Malin et al
Tanezumab, 10 g/kg 32.1 2.5 2007). It has also been observed that in genetically modied
Tanezumab, 25 g/kg 36.0 2.5 mice that overexpress artemin in the skin, sensitivity to both
Tanezumab, 50 g/kg 31.0 2.6 thermal and cold stimuli is increased (Elitt et al 2006).
Tanezumab, 100 g/kg 42.5 2.5
Tanezumab, 200 g/kg 45.2 2.6
Figure 3-5. Neutralizing nerve growth factor in patients with osteo-
arthritis signicantly reduces pain scores. At baseline, visual analog scale The number of inammatory pain mediators and modula-
scores for patients were obtained to assess the level of pain experienced while tors has grown steadily and now includes not only a vari-
walking. Patients then received either placebo or varying doses of tanezumab ety of small molecules such as bradykinin, prostanoids, ATP,
(10, 25, 50, 100, 200 g/kg) at the start of the study and again after 8 weeks. protons, and NO but also numerous cytokines, chemokines,
A decrease in the score represents a reduction in pain scores. (Data from
Lane NE, Schnitzer TJ, Birbara CA, et al 2010 Tanezumab for the treatment
and growth factors. The number of sources of such media-
of pain from osteoarthritis of the knee. New England Journal of Medicine tors has also increased and includes several or many immune
363:15211531.) cells, glial cells, and neurons. Finally, it has become clear that
these mediators have diverse mechanisms and sites of action,
including activation and sensitization of nociceptive termi-
outperformed the NSAID naproxen (Katz et al 2011). These nals, regulation of primary nociceptive phenotype, and in
ndings represent clear evidence of the important role that the spinal cord, presynaptic control of nociceptor transmit-
a signal mediator can play in patients with persistent pain. ter release and post-synaptic control of neuronal excitability.
However The development of tanezumab and other anti-NGF One of the most critical issues, of course, is to identify the
antibodies for widespread use was halted because of adverse relative importance of all these different mediators and mech-
events observed in a phase II trial involving OA. Here, wors- anisms in particular pain states. This may seem a difcult job
ening OA developed in 16 tanezumab-treated patients and given the known interaction of many inammatory media-
joint replacement therapy was required. The mechanisms tors. However, the success of one series of new agents, TNF-
behind these osteonecrotic events are unclear but potentially functionblocking molecules, as both disease-modifying and
suggest a modulatory role of NGF on joint homeostasis. pain-relieving agents in several autoimmune disorders, includ-
Alternatively, some level of hyponociception caused by exces- ing RA, and also the promise shown by anti-NGF antibodies
sive NGF neutralization may have resulted in accelerated give hope that this increased understanding of basic mecha-
progression of OA because of the overuse of damaged joints. nisms will translate into effective new therapies for painful
However, it seems that in more than half the cases, the bone disorders.
necrosis occurred in previously unaffected joints. Many other
trials in which NGF was neutralized have not observed such The references for this chapter can be found at www
severe adverse events, and it has been reported that repeated .expertconsult.com.
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Chapter Microglia: Critical Mediators
of Pain Hypersensitivity after
4 Peripheral Nerve Injury
Simon Beggs and Michael W. Salter

technique of Camillo Golgi in 1873. Golgis silver staining

SUMMARY revealed a new world of cellular structures, and it was imme-
Neuronglial interactions are increasingly recognized diately clear that other structures, distinct from neurons, were
as being key for physiological and pathological pro- present in the tissue samples. These non-neuronal structures
cesses in the central nervous system. Microglia in the had no place in the prevalent theory of the day and were put
spinal dorsal horn respond to injury to peripheral to rest by one of the foremost physiologists of the time, Rudolf
nerves by adopting a specic response state character- Virchow, who had previously dismissed these cells as Ner-
ized by up-regulation of the purinergic receptor P2X4. venkitt, or nerve glue (Virchow 1862). The glue cells were
In this P2X4R+ state, microglia release brain-derived deemed to not contribute to the physiological explanation
neurotrophic factor, which disinhibits neurons in the of mental phenomena (Exner 1894) and were subsequently
spinal nociceptive processing network. The transfor- ignored.
mation in processing caused by signaling of P2X4R+ Though recognized as structural elements in their own
microglia to nociceptive transmission neurons may right, this was the time of the advent of the neuron doc-
account for the main symptoms of neuropathic pain trine. This was established by the great Spanish histologist
in humans. and founder of modern neuroanatomy Santiago Ramon y
Cajal, who posited the nervous system as being made up of
discrete individual cells. It was in opposition to Golgi him-
self who had developed his reticular theory proposing that
INTRODUCTION every neuron in the entire nervous system is physically linked
Historical Perspective with its neighbors (ironically, a system that has more reso-
nance with the structure of astrocytes than neurons). Cajals
The world of pain research and therapy owes a great deal to improvement of Golgis pioneering staining techniques
the little-known German anesthetist and surgeon Carl Ludwig showed clear differentiation of neurons from neuroglia (now
Schleich (18591922) for two specic contributions. First, known as astrocytes and the source of Schleichs fascina-
Schleich was a pioneer of regional anesthesia and rened the tion), but it also revealed a further population of cells that he
technique considerably by introducing a new, safer method termed the third element (Andres-Barquin 2002). It was to
of inltration anesthesia, as detailed in his book Schmerzlose be the work of Cajals student Pio del Rio Hortega to unravel
Operationen (Painless Operations) (Schleich 1899). How- the mystery of this third element (Peneld 1965, Rezaie and
ever, within that book are contained his theories of brain Male 2002). By further rening the metallic impregnation
function, which make for remarkable reading. In what would techniques of Cajal, he was able to successfully stain this cell
be an extremely prescient proposal, Schleich rejected the population and in 1919 identify and dene it as two distinct
accepted neural network concept of the time being champi- populations that he named microglia and oligodendroglia
oned by Sigmund Exner (1894) and suggested an active role (Peneld 1965). This was an extremely controversial claim at
for glial cells. It was while listening to a piano recital that he the time, and debate raged between Rio Hortega and Cajal
was struck with inspiration and announced glia as a damper abo