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of PAIN.
OBJECTIVES
Nociceptors.
Primary afferent neuron
Dorsal horn Neurons
Ascending pathway
Descending control of pain
Pathophysiology
Peripheral Sensitization
Central Sensitization
Pain perception.
What is Pain.
Pain can be defined as the conscious awareness of
actual or potential tissue injury.
Pain is involving:
1. Nociceptors activation by mediators released from
injured tissue and nerves'.
2. Afferent transmission /conduction to the spinal cord and
processing within the dorsal horn and supra spinal
center.
3. Pain perception is depend on the net result of
interaction between Acendern in put and decendern
control.
4. In general, pain is an alarm mechanism to protect our
body.
Anatomy
Primary afferent neurons
1. Sensory afferent neurons have a unipolar cell body.
2. They are classified into 3 major groups (A,B,C),
according to the fiber size.
3. Group A is further sub-classified into 4
subgroups (A, A, A).
4. Sensory afferent that respond to noxious
stimulation include myelinated A, or unmyelinated
C- fiber.
5. Most A and all C fiber originate as free nerve
endings which is called NOCICEPTORS
Classification
of
Peripheral
nerve
5
1. NOCICEPTORS
What is a nociceptor?
H+
cold ATP
PGs warm
C-fibre
TRPVs ASICs EPs TRPs P2X
Na+, K+,
Ca2+
channels
sensitize, activate
Nociceptors;is characterized
by their response;
1. A-delta Mechanothermal nociceptors
Respond to mechanical and thermal stimuli.
display rapid conduction.
Produced first pain and well localized.
Ad fibers respond to this naciceptors.
A Fiber
Mechano Rapid Conduction Glu
Thermal
Nociceptors First Pain First
Pain
Secound Pain
C-Fiber
Slow Conduction Glu
Polimodal
Nociceptor sP
Secound
Pain
2. PERIPHERAL SENSORY
AFFERENT FIBERS
Anatomy of peripheral sensory nerve fibers
Large myelinated A
Small myelinated A
Unmyelinated C
A
C A
Two sensory afferent neurons
1. Large myelinated A fibers, very fast conduction velocity.
Respond to innocuous stimuli
2. Small myelinated A & C unmyelinated fibers, have slow
conduction velocity. Respond to noxious stimuli
Large
fibers A
Dorsal root
ganglion Dorsal Horn
A
Small
fibers
C Peripheral sensory
Nerve fibers
Modified by AHT
The Role of A fiber
Although in normal condition A fiber does not
response to noxious stimuli, but it plays a big
role in NORMAL SENSATION.
SP & CGRP
I NS
peripheral dorsal root IIo
endings ganlgia IIi
III
IV
A
heavily
low V
intensity
myelinated WDR
INPUTS
VIII
IX
REFLEXES
It is important to know that two
distinct responses to a noxious
stimulus FIRST PAIN and SECOUND PAIN
Modified by AHT
Role of nociceptors
and primary afferent
neurons are:
1. TRANSDUCTION
2. CONDUCTION
Noxious Soup
TRANSDUCTION PROCESS
(NOCICEPTORS ACTIVATION)
Local &
Vescular
Mediators- Action Potential
Ca++
Bradykinin,
Cytokines Peptides- TRP Na+
Histamine, sP, CCK,
5HT. CGRP
Traumatic
Tissue Mediators-
Injury K+, H+,
ATP,PGE
In Creased Neural
Synthesis Mediators- TRP Ca++
Pro Epine,
Inflammatory Norepine
Generator
Cytocaines
-(IL) 1
Potential
-IL-6
TRP (Transient Receptor Potential) Ion
Channel is a Transducer molecules. Modified by AHT
R. Sinatra 2007
Pain Perception
Pain
Descending
modulation Dorsal Horn
Transduction
Spinothalamic Peripheral
tract nerve
Trauma
Peripheral
nociceptors
Adapted from Gottschalk A et al. Am Fam Physician. 2001;63:1981, and Kehlet H et al. Anesth Analg. 1993;77:1049.
Modified by AHT
3. DORSAL HORN NEURONS
Dorsal Horn of Spinal cord
Plays a big role in pain perception
Is the first gate to control pain
Nociception (Pain) is born in DHN
Lehmann, K. A.: From the first stimulus to pain memory. UN. Cologne, 2000 21
Dorsal Horn Neurons
Is highly organized center of neurons
The place where afferent input is processed.
The place where terminal endings of primary afferent ( first
order neuron) and receiving neurons (second order neurons)
synapse.
Where interaction between excitatory and inhibitory
system.
Two types of second order nociceptive neurons are found in
DHN.
1. NS (Nociceptive-Specific Neurons )
2. WDR (Wide-Dynamic Range Neurons)
Targets of Primary Afferent Neurons in
the posterior gray (dorsal) horn
NS
WDR
Transmission at DH 23
NS : Respond exclusively to noxious stimuli from A
& C fiber.
WDR :
Respond to both noxious and innocuous stimuli.
May receive afferent input from skin, muscle, joint
and visceral nociceptors referred pain.
Low frequency stimulation of C fiber lead to
gradually increase WDR discharge, until
continuous discharge wind up.
These responsible by NMDA receptors, while
AMPA receptors responsible for short-lasting
depolarization (brief pain).
Neurotransmitters and receptors
on Dorsal Horn
Modulation at DH 25
NEUROTRANSMITTERS
Primary afferent neurons may release one or more excitatory
Amino acid (EAA) such as:
Glutamate
Aspartate, or
Peptide such as
Substance P Neurokinin A
CGRP (Calcitonin Gene-Relate Peptide)
CCK (Cholecystokinin) Somatostatin
Bombezine etc.
EAA mediated rapid short-duration depolarization of second
order neurons.
Peptides produce a delayed and long lasting depolarization.
4. ASCENDING PATHWAYS
Ascending Pathways
5 ascending pathways have been recognized.
1. SPINOTHALAMIC TRACT
Discriminative pathway location of pain
2. SPINORETICULAR TRACT
Emotional aspect of pain (suffering pathway)
3. DORSAL HORN COLUMN TRACT
Transmission of visceral pain
4. SPINOMESENCEPHALIC TRACT
Behavioral response
5. SPINOHYPOTHALAMIC TRACT
Sensationl from the skin, lips & sex organs
SSC FLC SPINOTHALAMIC TRACT
Neo Spino Thalamic Tract direct to
Cortex and
Thalamus
VPL MT
Thalamus SSC Localizing and
discriminative information withdrawal
reflex.
Hypothalamus Pleo Spino Thalamic Tract FLC (Frontal
and Pituitary Sympathetic
PAG Outflow Limbic Cortex) Affecting circulation,
Hypothalamic- respiration, endocrine, emotional,
Midbrain
Pituitary Outflow
behavioral responses (fear, anxiety,
LC
helplessness, avoidance).
Ascending Descending
Peripheral
Pathaways Pathaways
Nociceptor
Brainstem NRM
C-Fiber Sensory
Afferent
NSTT
Spinal Cord
Sympathetic
Efferent
A-Alpha Motor
Efferent
Response Cortical
- anxiety
- fear
- apprehension
Response Suprasegmental
- neurohumoral response
- catecholamines
- cortisol
- dll.
Response Segmental
- muclespasm
- vasospasm
- bronchospasm
- decreased gastrointestinal
motility
Response Local
-release pain substances
-inflammation
RESPONSES TO NOXIOUS STIMULI INDUCED BY AN ABDOMINAL SURGERY
5. DESCENDING MODULATING
PATHWAYS
Descending Modulating
Pathways
Those ascending pathways is modulated by descending
modulating pathways in several higher centers;
CEREBRAL CORTEX
THALAMUS
HYPOTHALAMUS
BRAINSTEM/ MIDBRAIN
Periaqueductal gray (PAG)
Nuclei raphe magnus
Locus ceruleus
Sub ceruleus
SPINAL CORD
SSC FLC
Cortex and
Thalamus
VPL MT
Hypothalamus
and Pituitary Sympathetic
PAG Outflow
Hypothalamic-
Pituitary Outflow
Midbrain
LC
Ascending Descending
Peripheral
Pathaways Pathaways
Nociceptor
Brainstem NRM
C-Fiber Sensory
Afferent
NSTT
Spinal Cord
Sympathetic
Efferent
A-Alpha Motor
Efferent
SEROTONIN
NEOREPINEPHRINE
Modulation
Descending Pain Control
Cortex
Brain Hypothalamus
Thalamus
Releases
Midbrain PAG Endogenous opioids
GABA
NE
Releases
Brain stem NRM Serotonin
NE
Inhibit
Spinal cord DHN WDR neurons Analgesia
NS neurons
NO BRAIN, NO PAIN
Role of DHN, is the place
where interaction between
afferent ascendern input
and descedern modulation
pain control.
1. MODULATION
2. TRANSMISSION
Perception Pain Perception
Pain
Medulation
Descending
modulation Dorsal Horn
Transduction
Spinothalamic Peripheral
tract nerve
Transmission Trauma
Peripheral
nociceptors
Adapted from Gottschalk A et al. Am Fam Physician. 2001;63:1981, and Kehlet H et al. Anesth Analg. 1993;77:1049.
Modified by AHT
PAIN PERCEPTION
How pain perception is processed, still obscured, and
Where pain perceptions in the brain still unclear.
Noxious perception?
Pain A number of theories:
Perception Brain
SS
1. Specificity theory by Descartes
(16 century)
SS Limbic Cortex
Sensory Cortex
Thalamus
2. Gate control theory by Melzack
and Wall (i965)
3. Sensitization theory by Woolf
et al (1990 an)
1. Specificity theory
Descartes
(17th Century)
Pain was
faithfully
transmitted
from
periphery to
brain
Modified by AHT
2.GATE CONTROL THEORY by MELZACK and Wall
Central Descending
Control Modulation
Large
fibers
+
+ Ascending Action
SG T
System
+
Small
fibers Dorsal Horn Gate
The Gate control theory of pain processing. T = Second-order transmission cell; SG = substantia
gelatinosa cell.
Modified by AHT
3.Sensitization theory by Woolf
After the injury sensitization in the periphery
and centrally is occurred. (Hyperalgesia and
allodynia).
Pain perception is the net process starting
from:
Nociceptor activation
Neural conduction
Spinal transmission
Noxious modulation
Limbic & frontal cortical perception
So, there are three
possibilities how do
we feel pain.
Noxious stimulus with Pain
Pain
Inhibition
CNS Modulation
Excitation
Example:
Nociception Stress Induced Analgesia
Inhibition
CNS Modulation
Excitation
Axon reflex
Primary afferent nerve
vessel
Nocicepto
Redness
r Swelling
Pain
Fever
PGE2
K+HH+ + HT Hist. PGI2 BK NOR
LTB4
Tissue Platelet Mast Membrane Kininogen
cell cell phospholopid
Tissue damage
Chemical intermediaries in nociceptive transduction
Nociceptors NO
Kinins
Vasculature
Neuropeptides
Primary Afferent Neurones
Prostaglandins
Sympathetic Efferent Neurones
7. Central Sensitization
NMDA RECEPTOR / CHANNEL
IS BLOCKED BY Mg ion
Ca
Na Na
NKr
Gly NMDA AMPA
Mg
Zn PCP
PKC
K K Dickenson, 1994
3 conditions are needed to release Mg
blockade.
NMDA is binding by Glu, Gly and Long depolarisation
Mg
SP Glu Glu
Ca
Na Na
NKr
Gly NMDA AMPA
DEPOLARIZATION
Zn PCP
PKC
K K Dickenson, 1994
When NMDA channel is open large of
Ca and Na influx into the cell
Mg
SP Glu Glu
Ca
Na Na
NKr Gly NMDA AMPA
DEPOLARIZATION
Zn PCP
PKC
K K
Increased excitability
Long term changes Ca
Cell death Dickenson, 1994
Central sensitization Processing in Spinal Cord
Inhibitory
Interneuron
Nociceptor NE
Terminal ending MU
Glu SP SP -
Glu SP
Post Synaptic Membrane of
the Spinal Sensory Neuron
Na+
Na+
Glu Ca++
Glu + SP
AMPA
Receptor
Receptor NK-1
Receptor
MU
-
Kainate
Receptor Second Messenger
Na+ Fast Prime Slow Prime Formation, (cAMP, PKA)
Hyperalgesia Normal
Response
No Pain
Allodynia
PERIPHERAL
ACTIVITY CENTRAL
SENSITIZATION
Decreased Increased
Nerve damage threshold to spontaneous
peripheral Expansion of activity
stimuli receptive
field
Inadequate postoperative
pain management
Pain disease
Sandkhler, J.: Preventing Pain Memory. MMW 2002; Special edition 2 62
VISCERAL PAIN
1. Neurophytiological thinking about pain in
general has been dominated by
Sherrington's approach.
PAIN AS PHYSICAL ADJUNCT OF A
PROTECTIVE REFLEX
IT HAS A SURVIVAL VALUE
(Sherrington 1926)
Cara pandang ini berlaku pada Sopratic Pain, tapi toh
pada Visceral Pain
Looks likely that Visceral Pain is not playing a role as
survival protection.
NATURE OF VISCERAL PAIN
2. 1. Is the most common form of pain produced by
disease and one of the most frequent reasons for
patients to seek medial attention.
2. Mechanism of visceral pain is less well understood
than somatic pain. (visceral pain research started
1990)
3. The more we know about mechanism of somatic
and visceral pain, the more realized that these two
processes, while heaving many common features,
also have important differences.
4. Visceral pain is evoked by a stimulus which may not
evoke in somatic pain.
5 CHARACTERISTIC OF VISCERAL PAIN
3. 1. Is not evoked from all visceral (liver, kidneys
or lungs do not have any sensory unless
adjacent structures are also affective.
2. Is not liked to visceral injury.
3. Is referred to other location.
4. Is diffuse and poorly location.
5. Is accompanied by method and autonomic
reflex.
THE DIFFERENT OF
SOMATIC AND
VISCERAL PAIN.
1. Visceral pain can not be evoked
from all visceral.
A NMDAr
Glutamate
A
Glutamate
+ Wind-up Brain
Gene induction
Inhibitory
GABA
-
Fibers
Glycine
Opioids
NA, 5HT
DECENDING CONTROL
Tissue
Injury
Descending
Cortex
Modulatory Systems
PAG
Opioids
Opioids
NRM LC
Opioids
Opioids
Dorsal homs
Modified by AHT
Two distinct sensations
(dual pain sensation)
Pain intensity
C fiber=second pain
later dull, somewhat
prolonged sensation
Time
Injury
Limbic Cortex
Sensory Cortex
Thalamus
Trauma
Descending Ascending
Pathway Pathways
Central Grey
Nociceptor
Mid Brain
Dorsal
Horn
Noxious Fiber
Spinal Cord
Motor Efferent
Adapted from Julius & Basbaum.
Nature 2001;413(6852):203
Pain Processing in Spinal Cord
Inhibitory
Interneuron
NE
Nociceptor
Terminal ending MU
Glu
SP SP -
Glu
SP
Post Synaptic Membrane of
the Spinal Sensory Neuron
Na+
Na+
Glu
Glu
Mg++
+ SP
Glu NMDA
AMPA
Receptor
Receptor NK-1
Receptor
MU
-
Kainate
Receptor Second Messenger
Na + Fast Prime Slow Prime Formation, (cAMP, PKA)
Modified by AHT
NOCICEPTIVE TRANSMISSION
Glu
( SP )
NMDA r
(CGRP)
NO
AA
Both have
free nerve
endings
Nociceptors
ACUTE (NOCICEPTIVE)
PAIN PATHWAYS
A nociception has at least 4 components
1. TRANSDUCTION
2. CONDUCTION
3. TRANSMISSION
3. MODULATION
4. PERCEPTION
Neuron III Persepsion
Transduction
Mechani Conduction/
cal Transmission
Transmission
Modulation
Neuron II
Therm
al
Neuron I
Chemic
al
Modified by AHT
1.TRANSDUCTION (NOCICEPTOR ACTIVATION)
Note!
Ca++ ion channels is a Generator Potential (gear)
Na+ ion channels is like accelerator (gas)
Ka+ ion channels is like breaker (rem) in automobile.
Transduction and Conduction Process
Ca2+
K+
K+
Na+
Poisons
mechanical , thermal , chemical
Tissue damage
Release of mediators
Hydrogen and potassium ions,
neurotransmitters, kinins, prostaglandins
Stimulation of nociceptors
Transmission to CNS
via afferent pathways
94
Pain
Tissue damage - inflammation
or nociceptive pain
Nerve damage - neuropathy
Headache/period
Central pain
Cancer pain
Co-existence
Acute
Chronic
Pain
Modulation
Descending Conduction
modulation Dorsal Horn Conduction
Ascending Dorsal root
input ganglion
Transduction
Spinothalamic Peripheral
tract nerve
transmission
Trauma
Peripheral
nociceptors
Adapted from Gottschalk A et al. Am Fam Physician. 2001;63:1981, and Kehlet H et al. Anesth Analg. 1993;77:1049.
Modified by AHT
Multimodal Analgesia
OPIOID
- Systemic
PERCEPTION - Epidural
- Subarachnoid
Pain Ketamin, Tramadol,
agonist
LOCAL ANESTHETIC
COX-2, COX-3?
- Epidural
MODULATION -Subarachnoid
Descending
modulation Dorsal Horn -Peripheral nerve block
Ascending
input CONDUCTION/
TRANSNISSION Steroids
LA
COX-1
Spinothalamic
COX-2
Peripheral
tract TRANSDUCTION
nerve
TRANSMISSION
Trauma
Peripheral
nociceptors