Acute and Neurophatic Pain

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14 Acute and Neuropathic Pain

P Honore and M F Jarvis, Abbott Laboratories, Abbott Park, IL, USA & 2007 Elsevier Ltd. All Rights Reserved. 6.14.1 6.14.2 6.14.3 6.14.3.1
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Introduction: Pain States Neuropathophysiology of Pain Experimental Pain Models Models of Acute Pain
Acute thermal pain Acute mechanical pain Acute chemical pain
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Models of Nociceptive Pain

Adjuvant-induced arthritis Unilateral inammation Models of osteoarthritic pain
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Models of Neuropathic Pain

Direct trauma to nerves Inammation/neuritis/nerve compression Diabetes Chemotherapy-induced neuropathic pain (vincristine/paclitaxel/platine)
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Clinical Trial Issues Translational Medicine in Pain Current Treatments Opioids Anti-Inammatory Drugs
Nonsteroidal anti-inammatory drugs Cyclooxygenase-2 inhibitors
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Analgesic Adjuvants
Amitriptyline Antiepileptics Pregabalin Antidepressants
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Unmet Medical Needs New Research Areas Neuronal Nicotinic Receptor Agonists Vanilloid Receptor Modulators Excitatory Amino Acid Receptor Antagonists Calcium Channel Modulators Cannabinoids Sodium Channel Modulators Purines
P1 receptor agonists P2 receptor antagonists
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Emerging Pain Targets Conclusions
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Acute and Neuropathic Pain
6.14.1
Introduction: Pain States
The International Association for the Study of Pain (IASP) denes pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.1 This denition clearly indicates that pain is a multidimensional experience. Pain is not homogenous and can be classied temporally as acute or chronic. Acute or physiological pain is an early warning against potential injury, a vital defense mechanism, whereas chronic pain does not play any useful role. As such, chronic pain can be very detrimental to the quality of life of an individual, disrupting sleep and normal living, and degrading health and functional capability.2 Chronic pain is one of the most common complaints for which individuals solicit medical attention. It can affect general and psychological health (as is evident by the high degree of comorbidity of chronic pain and emotional disorders such as depression and anxiety), and can also have deleterious socioeconomic consequences since it is often associated with the loss of work time and an increased use of healthcare resources. Published estimates of the prevalence of chronic pain typically range from 2% to 45% with 50% of respondents reportedly suffering from chronic pain.3 Interestingly, there was no signicant difference between genders and, as might be expected, the proportion and the degree of pain signicantly increased with age. Furthermore, 3340% of chronic pain patients included in their study were unhappy with medical examinations, medical tests, and treatments related to their chronic pain state.4 This lack of satisfactory pain relief in chronic pain patients was also identied in a 2004 Americans Living with Pain Survey conducted on behalf of the American Chronic Pain Association.5 In this study, 50% of the chronic pain patients surveyed felt that their pain was not under control. In the face of this growing unmet medical need is an increasing awareness of undertreated pain resulting in a more aggressive use of analgesics, especially opioids. As the population of elderly people continues to increase the demand for therapies to treat arthritis, pain associated with osteoporosis, and other painful diseases of the aged will also increase. These results clearly illustrate the need for better and more efcacious pain management medications, programs, and therapies. One of the greatest challenges in creating more efcacious medications for pain control has been the heterogeneity of the condition itself, including: the causes and underlying pathologies; the redundancies in pain perception; and the usefulness of current pharmacological therapies.
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Neuropathophysiology of Pain
The conceptualization of the neurobiology of pain has undergone continuous renement with increasing knowledge of multiple nociceptive targets and pathways.6,7 The psychophysical parameters used to describe nociceptive processing have thus been rened to differentiate acute withdrawal behaviors in response to dangerous (e.g., sharp or hot stimuli) stimuli in the environment (acute nociception) from increased sensitivity to mildly painful stimuli (hyperalgesia) or to otherwise innocuous stimuli (allodynia) (Figure 1).8 An increase in stimulus intensity in any sensory modality will eventually become noxious (Figure 1). Obviously, the sensation of noxious environmental stimuli (acute pain) is physiologically protective. However, following injury, this psychophysical function shifts such that previous noxious stimuli are now perceived as exceedingly painful (hyperalgesia). Additionally, tissue injury results in ongoing or spontaneous pain and the perception that normally nonnoxious stimuli are pain generating (allodynia). It is now
100 Hyperalgesia Pain sensation Allodynia
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Injury
Normal
Low Innocuous
Stimulus intensity
High Noxious
Figure 1 Psychophysical representation of hyperalgesia and allodynia sensory sensitivity. Following injury, being tissue or nerve injury, pain transmission and perception are changed so that a normally painful stimulus is going to be felt more painful (hyperalgesia) and a normally nonpainful stimulus is going to be felt as painful (allodynia). (Adapted from Cervero, F.; Laird, J. M., Pain 1996, 68, 1323.)
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well appreciated that distinct sensory mechanisms contribute to physiological pain, to pain arising from tissue damage (inammatory or nociceptive pain), and to pain arising from injury to the nervous system (neuropathic pain).9 Nociceptive pain is caused by the ongoing activation of A-d and C-nociceptors in response to a noxious stimulus (injury, disease, inammation) (Figure 2). It can be further classied into visceral pain (deep cramping sensation associated with referred pain), supercial somatic pain (skin; well-localized sharp, pricking, or burning sensation), and deep somatic pain (muscle, joint capsules, and bone; diffuse dull or aching sensation). Under normal physiological conditions, there is a close correspondence between pain perception and stimulus intensity, and the sensation of pain is indicative of real or potential tissue damage. As the nervous system becomes sensitized (responding more strongly than normal to peripheral stimuli), in addition to spontaneous pain, nociceptive pain is also associated with evoked hyperalgesic and allodynic conditions.1012 In general, nociceptive pain abates completely upon the resolution of injury if the disease process is controlled. Because of this, the use of disease-modifying therapies is being emphasized in the treatment of nociceptive chronic pain as illustrated in the treatment of rheumatoid arthritis not only by antiinammatory agents but also by biological therapies such as tumor necrosis factor-a (TNF-a) antagonists.13 Unlike nociceptive pain, neuropathic pain can persist long after the initiating injurious event has been removed and any damage has healed. This then leads to abnormal processing of sensory information by the nervous system. Neuropathic pain can be classied as peripheral (painful peripheral mononeuropathy and polyneuropathy) or central (post stroke, following spinal cord injury) and can originate from nerve injury following a wide array of conditions/ events, e.g., direct trauma to nerves, inammation/neuritis/nerve compression, diabetes, infections (herpes zoster, human immunodeciency virus (HIV)), tumors (nerve compression/inltration), toxins (chemotherapy), and primary neurological diseases.14,15 Following nerve injury, changes occur in the central nervous system (CNS) that can persist indenitely. Under these conditions of sensitization, pain can occur without a specic stimulus or can be disproportionate to the stimulus intensity. The sensation of neuropathic pain may also be constant or intermittent and is felt in many different ways (e.g., allodynia or hyperalgesia associated with mechanical or thermal stimuli but also spontaneous sensations such as burning, tingling, prickling, shooting, deep aching, and spasm).14,15
Normal pain Brain Descending inhibitions Nociceptors
Pathophysiological pain Brain Descending Peripheral inhibitions sensitization Nociceptors
Ascending pain pathways
Ascending pain pathways
A fibers
A fibers
Sprouting
Central sensitization Spinal cord Spinal cord
Figure 2 Normal and pathophysiological transmission of pain. Under normal conditions, pain stimuli such as noxious heat are transmitted from the peripheral site (e.g., skin or joints) through the nociceptive primary afferent bers to the spinal cord and the brain. Pathophysiological conditions are associated with peripheral and central sensitization. Peripheral sensitization can result from the sensitization of nociceptors by inammatory mediators, neurotrophic factors released during tissue damage or by inammatory cells. Peripheral sensitization is also associated with intense, repeated, or prolonged action potential generation in primary sensory afferents that is mediated by altered expression and activity of voltage-gated sodium and calcium channels. Consequences of peripheral sensitization are a lowering of the activation threshold of nociceptors and an increase in their ring rate. These changes result in the production of hyperalgesia and allodynia associated with nociceptive chronic pain. Central sensitization (long-lasting increases in dorsal horn neuron excitability and responsiveness) is associated with spontaneous dorsal horn neuron activity, responses from neurons that normally only respond to low intensity stimuli (altered neural connections following sprouting of Ab bers to supercial laminae) and reduction in central inhibition. Central sensitization is associated with persistent pain, hyperalgesia, allodynia, and the spread of pain to uninjured tissue. In addition, it reects a complex series of changes occurring in the spinal cord that may promote long-lasting increases in dorsal horn neuron excitability including the involvement of astrocytes and microglia activation.
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Tissue injury results in the release of pronociceptive mediators that sensitize peripheral nerve terminals (peripheral sensitization), leading to phenotypic alterations of sensory neurons and increased excitability of spinal cord dorsal horn neurons (central sensitization).7,9 Nerve injury may be associated with abnormal ring of the injured neurons, leading also to central sensitization and phenotypic changes in spinal cord neurons.16,17 In addition, descending supraspinal systems modulate nociceptive responses.18 A multitude of receptors, transmitters, second messenger systems, transcription factors, and other signaling molecules are now appreciated to be involved in pain pathways (Figures 2 and 3).6 As noted above, two mechanisms play a key role in the development and maintenance of chronic pain, namely peripheral and central sensitization.19 Peripheral sensitization can result from the sensitization of nociceptors by inammatory mediators (e.g., prostaglandin E2 (PGE2), serotonin (5HT), bradykinin, epinephrine, adenosine), by neurotrophic factors released during tissue damage (e.g., nerve growth factor (NGF)) or by inammatory cells (proinammatory cytokines including interleukin-1 (IL1)). Peripheral sensitization is also associated with intense, repeated, or prolonged action potential generation in primary sensory afferents that is mediated by altered expression and activity of voltage-gated sodium and calcium channels.6 Consequences of peripheral sensitization are a lowering of the activation threshold of nociceptors and an increase in their ring rate. These changes result in the production of hyperalgesia and allodynia associated with nociceptive chronic pain. In addition, peripheral sensitization plays also an important role in the development and maintenance of central sensitization.6,17 Central sensitization (long-lasting increases in dorsal horn neuron excitability and responsiveness) is associated with spontaneous dorsal horn neuron activity, responses from neurons that normally only respond to low-intensity stimuli (altered neural connections following sprouting of Ab bers to supercial laminae), expansion of dorsal horn neuron receptive elds, and reduction in central inhibition.2022 Central sensitization is associated with persistent pain, hyperalgesia, allodynia, and the spread of pain to uninjured tissue, i.e., secondary hyperalgesia due to increased receptor
Peripheral terminal primary afferent fiber
Dorsal root ganglion primary afferent cell body
Spinal cord
Descending systems or interneurons
Central terminal primary afferent fiber opioid TRPV1 TRPs mGLU Nav1.8 ASICs
SP CGRP TRPV1 ASICs
Nav1.8 TRPs P2X3

GLU CGRP NE 2 5HT NMDA GABA mGLU ENK CCKB opioid NK-1 ACh GABA-B SP
A1
P2X3
Nav1.3
SP BDNF GAL NPY Nav1.3
TNF IL1
CGRP-1
Post synaptic neuron
Glia
Figure 3 Pain transmission sites can be simply divided into two: the peripheral compartment (e.g., skin, muscle, organs) that encompasses primary afferent bers and dorsal root ganglions and the central compartment that includes the spinal cord and brain. A multitude of receptors, transmitters, second messenger systems, transcription factors, and other signaling molecules located all along pain transmission pathways are now appreciated to be involved in pain signaling. Tissue injury results in the release of pronociceptive mediators that activate and sensitize peripheral nerve terminals (peripheral sensitization) through various receptors/channels, leading to phenotypic alterations of sensory neurons with changes of receptor expression in DRG cell bodies and changes in neurotransmitter contents and increased excitability of spinal cord dorsal horn neurons (central sensitization) due to a variety of changes in receptor expression patterns and neurotransmitter release. In addition, interneurons and descending supraspinal systems modulate nociceptive responses either through excitatory or inhibitory effects. 5HT (serotonin), A1 (adenosine 1), a2 (alpha 2 adrenergic), ACH (acetylcholine), ASICs (acid sensing ion channels), BDNF (brain derived nerve growth factor), CCKB (cholecystokinin), CGRP (calcitonin gene related peptide), ENK (enkephalines), GABA, GAL (galanin), GLU (glutamate), mGlu (metabotropic glutamate receptors), Nav1.3 (sodium channels), Nav1.8 (sodium channels), NE (norepinephrine), NK-1 (neurokinin-1 receptor), NMDA (N-methyl-D-aspartate receptor), NPY (neuropeptide Y), opioid, P2X3 (ATP receptor), SP (substance P), TRP (transient receptor potential), and TRPV1 (vanilloid receptor 1).
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eld of spinal neurons. In addition, it reects a complex series of changes occurring in the spinal cord that may promote long-lasting increases in dorsal horn neuron excitability. This process is also know as wind-up in that the response of sensitized dorsal horn neurons is exaggerated relative to the normal situation.2022 While both peripheral and central sensitization play a role in nociceptive chronic pain, central sensitization clearly plays a key role in neuropathic pain. Thus, central sensitization also explains the observation that established pain is more difcult to suppress than acute pain because of the maladaptive changes that have taken place in the CNS.6,17 Interestingly, not only neurons, but also glia, e.g. astrocytes and microglia, as well as inltrating mast cells are involved in the generation and maintenance of central sensitization.23,24 In addition to the activation of pronociceptive inammatory and/or neurotrophic messengers noted above, the sensitization of the nervous system in response to chronic pain involves the alteration and/or activation of many neurotransmitter systems that have been extensively reviewed elsewhere.6,15 Chronic pain is mediated by altered neuronal excitability involving activation of sodium and calcium channels in both peripheral and spinal neurons. Additionally, there is enhanced glutamatergic activity and a concomitant decrease in GABAergic inhibitory neuromodulation at the level of the dorsal spinal horn.6,15 This altered neurochemical prole contributes to the heightened state of neuronal excitability (e.g., wind-up) and can be viewed as a shift in the balance of excitatory and inhibitory systems that also incorporates activation of intracellular signaling cascades (e.g., ras-mitogen-activated protein kinase (MAPK) pathway) and recruitment of neurotrophic neuropeptides including substance P, neuropeptide Y, and brain-derived neurotrophic factor (BDNF). These changes in spinal neuron neurochemistry are also accompanied by upregulation of specic excitatory amino acid receptors (e.g., a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and N-methyl-D-aspartate (NMDA)), as well as increased calcium and potassium ion channel activity. Taken together, chronic pain is associated with a large variety of deranged patterns of neurotransmission at multiple levels of the neuroaxis with considerable target and pathway redundancy. Thus, in the absence of ongoing injury, chronic pain can be viewed as a disease in itself. The enhanced appreciation of the many neurochemical and neurophysiological alterations in neuronal function associated with chronic pain has led to the development of both new preclinical models of pain and a variety of potentially useful therapeutic interventions.
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Experimental Pain Models
To facilitate the study of pain transmission and the characterization of novel analgesic compounds, an array of experimental animal pain models has been developed mainly in rodents, reecting all types of pain, from acute to chronic, somatic to visceral, and nociceptive to neuropathic and cancer-related pain. Depending on the model, pain measurements can encompass spontaneous pain behaviors as well as pain evoked by various sensory modalities. It is important to note that in rodents, measuring spontaneous pain is very difcult and is generally limited to the observation of quantiable nocifensive (pain-escape) behaviors such as hind paw lifting or altered grooming. However, experimental measures of evoked pain are well characterized and are analogous to clinical diagnostic methods. In the following overview, acute pain refers to pain that lasts from seconds to a day while chronic pain typically refers to experimental pain manipulations that persist for at least several days. In addition, this section will focus on the mostwidely used preclinical pain models. The majority of these animal models of pain were originally developed in rats. Except as noted below, essentially all have also been successfully carried out using various mouse strains including gene-disrupted (knockout) mice.25 However, signicant differences in the basal nociceptive sensitivity and analgesic response have been noted for different mouse strains serving to further complicate the interpretation of the knockout phenotype.26
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Models of Acute Pain
Animal models of acute pain allow the evaluation of the effects of potential analgesics on pain sensation/transmission in an otherwise normal animal. In addition, the same tests may be used to measure stimulus-evoked pain in animals with chronic inammation or nerve injury. Usually, these tests rely on an escape behavior/withdrawal reex or vocalization as an index of pain. The animals have control over the duration of the pain, that is, their behavioral response leads to termination of the noxious stimulus.
6.14.3.1.1 Acute thermal pain

Models have been developed to interrogate acute thermal pain sensitivity, using various means of applying a noxious heat stimulus to the paw or the tail of rodents. These models have been widely used in the characterization of opioid analgesics. Usually, latency to behavioral response is recorded and a cutoff is set to avoid any tissue damage to the
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animal. The tail-ick test involves the application of a focused heat (usually light) source on the tail until a tail-ick (rapid removal of the tail) reex occurs. This test has an advantage in that it does not involve repeated assessments of animal behavior, i.e., animals learning with time when the stimulus is going to be applied and anticipating the test. The hot plate assay uses a hot plate set at a xed temperature, usually 5055 1C. Latency to licking, shaking of hind limbs or fore limbs, in addition to latency to jump can be recorded and statistically analyzed for groups of animals. This assay can be difcult to standardize since the heat stimulus is not delivered in a controlled fashion. Possible sources of variability include differential exposure to the heated plat depending on how much weight the animal puts on each limb. Another approach to assess acute thermal pain is the use of a radiant heat source.27 Using this methodology, the temperature of the heat source applied to the hind paw increases over time until it reaches a painful threshold. Latency to hind paw withdraw is recorded and analyzed. In each test session, each animal is tested in three to four sequential trials at approximately 5 min intervals to avoid sensitization of the response. One of the advantages of this method versus the tail-ick assay is that both paws can be tested. This important control has proven a useful behavioral assessment in models of unilateral inammation or nerve injury, the contralateral paw serving as control for the injured paw. In addition, in this assay, rats are conned in plastic chambers but not manually restrained as in the tail-ick assay or in the immersion tests (see below), decreasing the stress level of the test subjects. This method also uses a heated (30 1C) glass test surface to prevent paw cooling and to minimize sensitization artifacts. Acute thermal pain can also be evaluated using a xed temperature (4550 1C) water bath and assessment of latency to withdraw of a hind limb or tail from the hot water. One of the advantages of this method is that the water bath can be set at various temperatures and it can be less sensitive to environmental conditions. However, this assay requires handling of the animals when testing for nociceptive behavior, making this measure highly dependent on experimenter experience/comfort handling/restraining animals by hand. This method can also be used to test for reactivity to cold, using a 4 or 10 1C water bath and recording latency to withdraw as an index of pain. Another method uses a cold plate cooled by cold water circulating under it. Latency to nociceptive behavior or duration of guarding behavior can be recorded. As for the hot plate assay, the cold plate test has the advantage of not requiring animal restraint. However, depending on the position of the animal paw on the plate (or just above it), the cold stimulation can be very variable. Another widely used method is application of a drop of cold acetone on the plantar skin of animals resting on an elevated mesh oor. Acetone produces a distinct cooling sensation as it evaporates. Normal rats will not respond to this stimulus or with a very small response (in amplitude and duration) while nerve-injured rats will almost always respond with an exaggerated response.
6.14.3.1.2 Acute mechanical pain

Models have been developed to interrogate acute mechanical pain/sensitivity, using various means of stimulating the paw or the tail of a mouse or a rat. A common method for the assessment of acute mechanical pain is determination of withdrawal thresholds to paw/tail pressure using the Randall Selitto test.28 This apparatus allows for the application of a steadily increasing pressure to the dorsal surface of the hind paw/tail of a rat via a dome-shaped plastic tip. The threshold (in g) for either paw/tail withdrawal or vocalization is recorded. Usually, two or three measurements are conducted on each paw or tail. This apparatus was designed originally for measuring mechanical sensitivity of inamed paws and its use in normal noninamed paws can produce great variability in the response, depending on the location of the stylus (soft tissue between the metatarsal/bone/joint). It is worth noting that training helps generate a more stable response with this assay. Another approach for assessment of acute mechanical pain is to use a pinprick, applying painful pressure to the plantar surface of the hind paw. This is similar to the pricking pain test done during the neurological examination in patients. The behavior can be measured by the duration of paw lifting following the pinprick application or recorded as a frequency of withdrawal (percentage of response to the pinprick in 10 trials). Finally, mechanical hypersensitivity can also be tested with von Frey monolaments. These are a series of hairs/ nylon monolaments of various thicknesses that exert various degrees of force when applied to the planter surface of the hind paw. Responses can be quantied as percentage response or duration of response to a given monolament force applied several times, or mechanical threshold can be determined using the updown method.29
6.14.3.1.3 Acute chemical pain

Usually, when studying acute chemical pain, behaviors such as inching, biting, or licking the injected paw are recorded at various time points following the injection of a chemical irritant (capsaicin, formalin, PGE2, mustard oil, ab-methylene ATP). The duration of the nociceptive behavior as well as the number of behaviors can be quantied and analyzed. Two models are mostly used to study acute chemical pain: nocifensive behaviors following injection of
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capsaicin or formalin into the hind paw.30 Doses of capsaicin can vary from 1 to 10 mg per 10 mL injected to the dorsal surface of the rat hind paw. The injection of capsaicin is immediately followed by an intense period of nocifensive behaviors that are usually recorded for 5 min following capsaicin injection. Following formalin injection (usually 5% per 50 mL) into the dorsal or sometimes plantar surface of the rat hind paw, a biphasic behavioral response can be observed. Phase I of the formalin response is dened as the period of time immediately following injection of formalin until 10 min after the formalin injection and corresponds to acute thermal pain by direct activation of nociceptors by formalin. Following a quiet period of little or no nocifensive behavior, the second phase of the formalin response can be observed (2060 min post formalin injection) that corresponds to a more persistent inammatory state.
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Models of Nociceptive Pain
Models of nociceptive pain are dened as models of pain following tissue injury induced by trauma, surgery, inammation, and cancer. As stated above, spontaneous pain in these models is difcult to measure. However, evoked pain behaviors have been well characterized and can be induced by the methods described above in the acute pain section. The focus of this section will be on models of nociceptive pain, mimicking as closely as possible rheumatoid arthritis and osteoarthritis clinical conditions since they have been the most studied and widely used. Models of postoperative pain or cancer pain will not be described, as they are recent and still under validation.
6.14.3.2.1 Adjuvant-induced arthritis

Experimental arthritis is generated by an intravenous injection of complete Freunds adjuvant (CFA) at the base of the tail. The development of the joint inammation is progressive and dramatic, leading to a multijoint arthritis with dramatic swelling and permanent joint tissue destruction.31 In this model, it is clear that the animals are in chronic pain, all their joints are swollen, they have decreased appetite, they limp, and have lower threshold for limb withdrawal or vocalization to paw pressure/joint manipulation. This model is rarely used today as the polyarthritic rat has signicant systemic disease with abnormal hunchback posture and piloerection.
6.14.3.2.2 Unilateral inammation

To further study inammatory pain, various models have been developed to induce a localized inammatory reaction by injecting various substances, e.g., formalin, carrageenan, or CFA into the paw or the joint. Following the initial injection, pain can be measured minutes to days later, at the site of inammation or away from the primary site of injury. Usually, the inamed paw/joint becomes very sensitive to both thermal and mechanical stimuli while the contralateral paw remains normal. Sometimes, secondary mechanical hypersensitivity can also develop on the contralateral side as observed 2 weeks following carrageenan injection into the knee joint when testing on the contralateral paw. These models of more localized inammation/inammatory pain have been widely used in pain research to test the effects of potential analgesic compounds but also in electrophysiological and gene expression studies to determine the plastic changes that initiate/maintain chronic inammatory pain.
6.14.3.2.3 Models of osteoarthritic pain

More recently, models have been developed to mimic osteoarthritic (OA) pain observed in the clinic. Contrary to rheumatoid arthritis (RA) and the models of inammatory pain, OA in the clinic and in animal models is not associated with a large amount of inammation. In addition, to mimic more closely the clinical situation, pain evaluation in OA pain models relies on functional measures such as weight bearing or grip force of the affected limb rather than evaluation of withdrawal latencies to thermal or mechanical stimuli. Two models have been widely used, intraarticular administration of sodium monoiodoacetate (MIA) into the knee and partial meniscectomy.32 Contrary to what is observed in the polyarthritic rat, no changes in body weight were observed over a 4-week period after either iodoacetate injection or partial medial meniscectomy. In addition, the general health of the animals is good with no signs of spontaneous nociceptive behavior, impaired locomotion, or distress. Furthermore, both iodoacetate injection and partial medial meniscectomy in the knee joint of the rat induced histological changes and pain-related behaviors characteristic of clinical OA. Although the behavioral changes and histology both worsened over time, the majority of the pain responses were apparent within one week of surgery or iodoacetate injection. It is important to note that the pain behaviors are less pronounced in the surgery model than in the MIA model and that these ndings agree with the clinical situation. Indeed, magnetic resonance imaging (MRI) studies have shown that although meniscal lesions in humans are common, they are also rarely associated with pain.
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6.14.3.3
Models of Neuropathic Pain
6.14.3.3.1 Direct trauma to nerves

To mimic nerve injury observed in the clinic, a number of different animals models have been developed. One of the most studied models is the L5L6 spinal nerve ligation (SNL, Chung model) (Figure 4) model.33 In this model, following sterilization procedures, a 1.5 cm incision is made dorsal to the lumbosacral plexus, the paraspinal muscles are separated from the spinous processes, the L5 and L6 spinal nerves are isolated, and tightly ligated with 30 silk thread. Usually the animals are allowed to recover from surgery for 7 days before being tested for mechanical allodynia using von Frey monolaments (updown method or percentage response to 10 applications of innocuous or noxious von Frey monolament). While the spinal nerve injured rats also develop cold allodynia and thermal hyperalgesia, they have a greater degree of mechanical allodynia and most pharmacological studies with these animals have involved mechanical allodynia endpoints. Another widely used model of direct nerve injury is a partial nerve ligation model (PNL) (Figure 4).33 The sciatic nerve is exposed unilaterally, just distal to the descendence of the posterior biceps semitendinosus nerve from the sciatic. The dorsal 1/31/2 of the nerve thickness is then tightly ligated with an 80 silk suture. Following injury, these animals develop guarding behavior of the injured hind limb suggesting the possibility of spontaneous pain. In addition, the animals develop mechanical allodynia as well as thermal hyperalgesia and bilateral mechanical hyperalgesia.
6.14.3.3.2 Inammation/neuritis/nerve compression

Neuropathic pain can also result from inammation around peripheral nerves and peripheral nerve compression. Two preclinical models have been developed to attempt to mimic this phenomenon. The rst model is the chronic constriction injury (CCI) (Bennett model) (Figure 4) of the sciatic nerve model.33 In this model, a 1.5 cm incision is made 0.5 cm below the pelvis. The biceps femoris and the gluteus supercialis are separated and the sciatic nerve exposed, isolated, and four loose ligatures (50 chromic catgut) with 1 mm spacing are placed around it. CCI animals develop mechanical allodynia, cold allodynia, and thermal hyperalgesia. When compared to the SNL injured animals, CCI animals do develop thermal hyperalgesia and cold allodynia to a greater extent. The second model, developed more recently, is the SIN model or zymosan-induced sciatic inammatory neuritis.34 In this model, a chronic indwelling perisciatic catheter is used to inject zymosan around the sciatic nerve. After aseptic exposure of the sciatic nerve at midthigh level, the gelfoam is threaded around the nerve so as to minimize nerve displacement. Suturing and insertion of a sterile dummy injection tube during implantation maintained catheter patency and ensured replicable drug delivery close to the nerve. After anchoring to the muscle, the external end is tunneled subcutaneously to exit 1 cm rostral to the tail base. After removal of the dummy injector, the external end of the silastic tube is protected. Usually, catheter placement can be veried at sacrice by visual inspection. The catheter
L6 SNL L5 L4
Spinal cord
DRG
Sciatic
CCI
L4
PNL
Peroneal Tibial Sural
Figure 4 Animal models of neuropathic pain. This schematic illustrates the three main rodent models of neuropathic pain associated with direct nerve injury; the L5L6 spinal nerve ligation (SNL) model (Chung model), the chronic constriction injury (CCI) of the sciatic nerve model (Bennett model), and the partial nerve ligation (PNL) model (Seltzer model).
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is used for a single injection 45 days after surgery conducted in freely moving rats. In this model, perisciatic zymosan injection induces unilateral mechanical allodynia at low dose and bilateral mechanical allodynia at high dose. Interestingly, the same high dose injected into gelfoam in neighboring muscles does not induce mechanical allodynia, suggesting that immune activation must occur in close proximity to peripheral nerves to create allodynia and that zymosan spread to systemic circulation cannot explain allodynia created by perisciatic zymosan. Interestingly, no thermal hyperalgesia is observed in this model.
6.14.3.3.3 Diabetes
Another major cause of neuropathic pain in the clinic is neuropathic pain observed in diabetic patients. In rodents, this is mimicked by streptozotocin (STZ) injection to induce diabetes and subsequent neuropathic pain symptoms.33 Usually, diabetes is induced by a single injection of STZ (75 mg kg 1 intraperitoneal). Diabetes is conrmed by testing for blood glucose levels. Not all animals show signs of neuropathic pain immediately following STZ administration. Generally it takes usually between 4 and 8 weeks to observed neuropathic pain symptoms, mostly mechanical allodynia assessment with von Frey monolaments, in a group of streptozotocin-treated rats.
6.14.3.3.4 Chemotherapy-induced neuropathic pain (vincristine/paclitaxel/platine)

The last type of neuropathic pain models are chemotherapy-induced neuropathic pain models. Cancer-related pain is a signicant clinical problem that will likely increase in its extent as the average lifespan continues to rise and cancer therapies continue to improve. The two main sources of cancer-related pain are that from the malignancy itself and from the treatments utilized to alleviate the cancer (surgery, radiation, and chemotherapy). Peripheral neuropathy and subsequent neuropathic pain related to chemotherapeutic treatment can be dose limiting, and the pain is often resistant to standard analgesics. To date, no one drug or drug class is considered to be both a safe and effective analgesic in the treatment of chemotherapy-induced pain, and three preclinical models of chemotherapy-induced neuropathic pain have been recently developed to further our understanding of the pathophysiology of such neuropathic pain states. Chemotherapy-induced neuropathic pain can be induced by the injection of either vincristine, platine, or paclitaxel.33 Depending on the experimental protocol, they can be injected as a bolus, for several days or weeks or as a continuous intravenous infusion using osmotic pump. Interestingly, as observed in the clinic, thermal hyperalgesia is not observed in these animals. However, both mechanical allodynia and cold allodynia are observed. The differential efcacy of analgesic medications for different types of pain that is seen in the clinic is also observed in animal pain models. For example, while opioid analgesics like morphine (Figure 5) are potent and efcacious in all animal pain models, anti-inammatory agents such as ibuprofen and celecoxib (Figure 5) are most potent and effective in animal models associated with inammation, and anti-epileptics like lamotrigine and gabapentin (Figure 6) are most potent and efcacious in animal models of neuropathic pain (Table 1). As preclinical models of the various forms of pain appear to have selective and differential predictive validity for efcacy in the clinical setting, they should be useful in determining if new chemical entities (NCEs) with a novel molecular mechanism have the promise to be broadspectrum analgesics.
6.14.4
Clinical Trial Issues
Traditionally, the assessment of novel analgesics has been based on methods and models based on the clinical utility of opioid analgesics.14 Many of the endpoints measured involve the use of self-report methodologies including the classical visual analog scale (VAS) with which patients rate their pain from a score of 0 (no noticeable pain) to 10 (worst pain imaginable). For the specic assessment of neuropathic pain, clinical studies have used tools like the McGill Pain Questionnaire, Neuropathic Pain Scale, and the Neuropathic Pain Symptoms Inventory. While the use of many of these analgesic endpoints has been validated in the clinical setting, the use of specic combinations of these scales may be useful to enhance the sensitivity of clinical outcomes for new analgesic compounds. Clinical trial designs often employ parallel placebo-controlled and randomized withdrawal types of experimental manipulations.14,35 The majority of these designs have been well validated using opioids; however, the relative utility in assessing novel analgesics that target specic aspects of chronic pain (e.g., neuropathic allodynia) await further evaluation (e.g., non-NSAID (nonsteroidal anti-inammatory drug) mediated analgesia in the third molar extraction model). A number of nociceptive tests have also been used in experimental clinical trials including acute heat sensitivity, topical and intradermal capsaicin, heat/capsaicin combinations, and quantitative sensory testing using both mechanical and thermal stimuli.36,37 Some of these tests can also be coupled to other functional readouts such as functional MRI
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HO O H NCH3 HO Morphine
HO H3C O OH NCH3 O Oxycodone O CH3 CH3 H3C Ibuprofen SO2NH2 COOH CH3O N
O N
H HO CH3O
CH2N(CH3)2
Fentanyl
Tramadol
Cl CH3
COOH O O
CH3
COOH Indomethacin Aspirin
O H3C N O N F F Celecoxib F Rofecoxib H3CO2S
Figure 5 Opioid analgesics, nonsteroidal anti-inammatory analgesics, and cyclooxygenase-2 (COX-2) inhibitors.
H3C
CH3 N
NH2 CO2H
NH2 CO2H
NH2
Gabapentin
Pregabalin
Carbamazepine
N CH3 CH3 Amitriptyline
NH2 N NH2 N N Cl Cl S O NH CH3 Duloxetine
Lamotrigine
Figure 6 Analgesic adjuvant agents.
(fMRI) and nerve conduction velocity assessments to further enhance measurements of drug action.38 For example, in assessing the acute antinociceptive effects of remifentanyl, the apparent sensitivity of fMRI analysis of human cortical oxygen utilization was signicantly greater than patients subjective ratings using traditional VAS scales. The use of fMRI coupled with experimental pain models like the capsaicin-evoked secondary hyperalgesia model may provide a reliable early assessment of novel analgesic efcacy. Many of these techniques have received clinical validation using opioids and are now being used to characterize mechanistically novel therapeutics.
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Table 1 Effects of clinically used analgesics in preclinical models of acute, nociceptive, and neuropathic pain; relative analgesic efcacy of clinically useful analgesics in experimental pain models in the absence of psychomotor side effects. Data derived from both in house and literature values (see text)
Acute pain T
Morphine Ibuprofen Celecoxib Gabapentin Lamotrigine 2 0 0 0 2
Nociceptive pain C
2 1 1 1 2
Neuropathic pain CFA

5 5 5 3 3
F
3 2 2 3 3
Car
4 5 5 2 2
OA
4 2 5 2 2
RA
5 NT 1 NT NT
SNL
2 2 2 5 5
CCI
3 3 3 5 4
Vinc
3 0 0 3 3
Scale: 0, no effect; 1, o20% effect; 2, 2040% effect; 3, 4060% effect; 4, 6080% effect; 5, 80100% effect, NT, Not tested. Abbreviations: T, tail ick; C, abdominal constriction; F, formalin; Car, carrageenan; CFA, complete Freunds adjuvant; OA, osteoarthritis; RA, rheumatoid arthritis; SNL, spinal nerve ligation; CCI, chronic constriction injury; Vinc, vincristine.
6.14.4.1
Translational Medicine in Pain
A major issue in all aspects of drug discovery is the extent of predictivity of the preclinical animal models used to characterize NCEs to the clinical situation. Of all areas of research, based on validation with opioids and nonsteroidal anti-inammatory drugs (NSAIDs), pain models were always considered highly robust. However, the recent failure of multiple NCEs targeted for the neurokinin-1 (NK-1) or substance P receptor has raised serious concerns about the translation of preclinical analgesic data to analgesic efcacy in patients.39,40 Structurally diverse NK-1 antagonists from several companies were evaluated clinically for acute pain (third molar extraction, migraine, or diabetic neuropathy).40 While these NCEs attenuated nociceptive responses sensitized by either inammation or nerve damage, they exhibited little effect on baseline (acute) nociception in preclinical models of pain. However, these same NCEs failed to demonstrate signicant analgesic efcacy in early clinical trials. This situation has led to the re-evaluation of both the predictability of the preclinical animal models as well as the utility of clinical trial designs that were customized to assess analgesic by opiate and/or NSAID mechanisms. Is should also be noted that with the exception of the formalin model described above, animal pain models largely depend on stimulus-evoked pain behaviors as experimental endpoints. Consequently, assessments of ongoing nociception that are the foundation of most clinical studies are not modeled very well preclinically. It remains unclear whether the disconnect between the preclinical and clinical data for NK-1 antagonists reects species-dependent roles of substance P in chronic pain or an imprecision in relating the nociceptive state of experimental animals to that of humans. Clearly, additional research is needed to adequately resolve these translational research issues for NK-1 antagonists. This issue highlights the practical need for the development of accurate and cost-effective translational medicine approaches to assess analgesic efcacy such as the coupling of fMRI studies with pain modeling in clinical studies described above.38
6.14.5
Current Treatments
Currently available analgesic agents can be broadly categorized as nonopioid analgesics (acetaminophen and NSAIDs), opioid analgesics (morphine and fentanyl), and adjuvant analgesics or coanalgesics (e.g., antiepileptics, anesthetics, and antidepressants). Nonopioid analgesics are mostly used to relieve mild to moderate nociceptive pain, adjuvant analgesics are used to relieve neuropathic pain, and opioid analgesics are used to treat severe pain of all origins, depending on the dose prescribed. Based on a number needed to treat analysis, a variety of opioid medications including fentanyl and oxycodone produce equivalent analgesic efcacy in neuropathic pain as compared to gabapentin, tramadol, and analgesic adjuvants like tricyclic antidepressants and anticonvulsants.41 The primary adverse event associated with chronic opioid therapy is decreased gastrointestinal (GI) motility. Respiratory depression and opioid dependence, which are routinely cited as a major issue in the use of opioids for pain therapy, are signicantly less prevalent in chronic pain patients. This nding has led to ethical concerns related to patients not being given sufcient pain medication due to legal issues with drug scheduling.35,42 While currently available analgesics have therapeutic utility in different pain states, all suffer from drawbacks in clinical use. The opioids can produce tolerance and dependence, constipation, respiratory depression, and sedation.
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The NSAIDs are associated with GI side effects and increased bleeding time, and do not effectively ameliorate severe pain. It has been estimated conservatively that 16 500 NSAID-related deaths occur among patients with rheumatoid arthritis or osteoarthritis every year in the USA.43 The development of selective COX-2 inhibitors (e.g., celecoxib and rofecoxib (Figure 5)) offered NSAID-like analgesia with the potential for diminished GI side effects. However, in light of the withdrawal of rofecoxib from the market, the cardiovascular safety of this class of analgesics is questionable.44 Adjuvant agents, e.g., gabapentin, lamotrigine, and amitryptiline, whose mechanism of action may be primarily mediated via a nonselective block of sodium channels, are associated with CNS and cardiovascular side effects. Currently available analgesics also have limited utility in the treatment of neuropathic pain. The anticonvulsant adjuvant gabapentin (Figure 6), which also has a poorly dened mechanism of action, has demonstrated clinical utility in the treatment of some forms of neuropathic pain.45 Thus, there is a signicant unmet medical need for safer and more effective analgesic agents.
6.14.5.1
Opioids
Opioid analgesics produce their effects by binding and activating the opioid receptor subtypes (e.g., m, d, k receptors) in the CNS.6 The cloning and characterization of the major opioid receptor subtypes (m, OP1; d, OP2; and k, OP3) has stimulated signicant basic and clinical research to discover new opioids with improved target selectivity, safety, and efcacy. Moreover, each of these opioid subtypes has been further subdivided into putative subtypes, and an orphan member of this family, ORL-1 (OP4), has also been described.46 Given the anatomical distribution of the opioid receptors in the CNS, opioid analgesics can block pain transmission from the periphery to the spinal cord by blocking neurotransmitter release from the primary afferent bers and by directly decreasing activation of postsynaptic dorsal horn neurons. The broad spectrum analgesic efcacy of the opioids, like morphine, fentanyl, and oxycodone (Figure 5), coupled with the fact that these agents do not show analgesic ceiling effects makes opioid compounds the mainstay in the control of moderate to severe pain.46 The analgesic actions of opioid drugs are mediated at multiple sites of action including primary sensory afferent neurons, the dorsal horn of the spinal cord, and sites within the brain such as the brainstem and midbrain. This multitude of opioid interactions also contributes to the side effects associated with opioid analgesic therapy including dependence, tolerance, immunosuppression, respiratory depression, and constipation.41 Opioid dose titration can be achieved to manage some nociceptive conditions; however, this strategy does not provide full efcacy in all chronic pain syndromes such as cancer and neuropathic pain.35,41 In addition, acting at higher brain centers, opioid analgesics can decrease pain transmission from the spinal cord to the brain, alter the limbic system, and increase descending inhibitory pathways to modulate pain transmission at the spinal level. While nociceptive pain is generally more responsive to opioid analgesics than neuropathic pain, nearly all types of pain respond to the right dose of opioid analgesics. Opioid analgesics are usually recommended to treat moderate to severe pain that does not respond to nonopioid analgesics alone and are often prescribed in combination with nonopioid analgesics. They do play a key role in the treatment of acute pain (postoperative pain), breakthrough pain, cancer pain, and some types of chronic noncancer pain.35 However, the use of opioid analgesics is associated with side effects such as sedation, confusion, respiratory depression, constipation, nausea, and vomiting that can limit their utility. More recently, a number of controlled release or extended release formulations of opioids have been developed in an effort both to enhance the analgesic coverage of these medications and to reduce the severity of the adverse events. The discovery of the opioid receptors in 1973 and their subsequent cloning has conceptually provided the tools necessary to develop receptor subtype selective NCEs that may improved efcacy and/or reduced side effect liabilities that would make them more useful analgesic agents. However, since 1975, more than $3 billion has been spent on research to nd such improved NCEs but none has lived up to its preclinical promise in the clinical situation.
6.14.5.2
Anti-Inammatory Drugs
6.14.5.2.1 Nonsteroidal anti-inammatory drugs

The primary mechanism of action of NSAIDs is the blockade of prostaglandin synthesis via inhibition of the cyclooxygenase enzymes (COX-1 and COX-2). NSAIDs like aspirin, diclofenac, and ketorolac (Figure 5) have antiinammatory, antipyretic, and analgesic effects, and their anti-inammatory effects can indirectly relieve nociceptive pain by reducing inammation and tissue swelling, although potency across these effects can be compound dependent. These characteristics make them particularly efcacious is nociceptive pain conditions associated with peripheral inammation.
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6.14.5.2.2 Cyclooxygenase-2 inhibitors

Recently, selective inhibitors of COX-2 (the COX enzyme isoform inducible by inammation), e.g., celecoxib and rofecoxib (Figure 5), have demonstrated similar efcacy to classical NSAIDs with reportedly fewer GI side effects at therapeutic doses.47 However, this is controversial and these agents have also recently been associated with a signicant increase in the risk of cardiovascular disease that has brought the entire class under intense scrutiny with rofecoxib having been withdrawn from the market.44,48 As stated above, NSAIDs relieve mild to moderate pain associated with trauma, surgery, cancer, and arthritis. They are especially effective for certain types of somatic pain such as muscle and joint pain, sprains, bone/dental pain (tooth extraction), inammatory pain, osteoarthritic pain, and in combination with disease-modifying therapies in rheumatoid arthritic pain.49
6.14.5.3
Analgesic Adjuvants
Adjuvant analgesics have a primary indication other than pain but have demonstrated analgesic effects in particular pain conditions. Antiepileptic drugs such as gabapentin, amitriptyline, carbamazepine, and lamotrigine (Figure 6) are one type of adjuvant analgesic and are used primarily in the treatment of neuropathic pain.45 While it is hypothesized that their analgesic effects are due to their ability to reduce membrane excitability and tone down a hyperexcitable nervous system, their exact mechanism(s) of action remains unclear and not all antiepileptic drugs are good analgesics. As a class, they are most efcacious at treating peripheral neuropathic pain, postherpetic neuralgia, trigeminal neuralgia, and diabetic neuropathic pain.50
6.14.5.3.1 Amitriptyline
Amitriptyline is a tricyclic compound that has been approved for treatment of major affective disorders (e.g., depression) since the 1950s.51 The antidepressant actions of amitriptyline generally are associated with blockade of the uptake of serotonin and norepinephrine in the CNS; however, amitriptyline possesses a multiplicity of other distinct pharmacological activities, e.g., antagonist actions at histamine, muscarinic, a1-adrenergic, and serotonin receptors at namomolar concentrations and at a number of ion channels (e.g., sodium, calcium, and potassium) at micromolar concentrations.52,53 Amitriptyline also has micromolar afnity for blocking the uptake of the antinociceptive and antiinammatory purine adenosine.52 In addition, amitriptyline has peripheral anti-inammatory/analgesic actions in several in vivo models that are associated with acute, local delivery of low concentrations of amitriptyline. Many of these pharmacological activities are likely to contribute to its analgesic and anti-inammatory actions.
6.14.5.3.2 Antiepileptics
Recent data suggest that newer antiepileptic drugs such as gabapentin or lamotrigine (Figure 6) are better alternatives to older agents of this class. Lamotrigine has been shown to be effective in patients with trigeminal neuralgia, complex regional pain syndrome, and neuropathic pain associated with multiple sclerosis and HIV infection.54,55 In addition, it has been shown that gabapentin provides pain relief in diabetic neuropathic pain conditions and postherpetic neuralgia; it also has a more favorable side effect prole compared to other neuropathic pain agents.55 Open-label studies suggest that gabapentin also may be useful in the management of trigeminal neuralgia, central pain, phantom limb pain, and neuropathy associated with HIV infection. Common side effects of antiepileptic drugs as a class include sedation, mental clouding, dizziness, nausea, or unsteadiness, and patients need to start at low doses and go through a slow titration in order to diminish the risk of side effects.
6.14.5.3.3 Pregabalin
Pregabalin (Figure 6), an alkylated analog of GABA, is a more potent anticonvulsant than gabapentin and has shown enhanced analgesic potency as well.56 Pregabalin is clinically effective in pain associated with diabetic neuropathy and postherpetic neuralgia. The enhanced potency of pregabalin relative to gabapentin appears to be related to pharmacokinetic properties rather the mechanism of action. In this regard, the analgesic mechanism(s) for these anticonvulsant compounds has not been denitively determined. Recent data indicate that these GABA analogs bind the a2d subunit of voltage-gated calcium channels with high afnity.57 However, it should be noted that binding to the a2d subunit is not likely to fully account for the analgesic properties of gabapentin or pregabalin.58
6.14.5.3.4 Antidepressants
In addition to antiepileptic drugs, tricyclic antidepressant drugs like amitriptyline are also used as adjunct analgesics in the treatment of neuropathic pain.14,45 While other antidepressant medications such as selective serotonin reuptake inhibitors (SSRIs) have not proven to be particularly efcacious in treating neuropathic pain, some of the newer
340
combination serotoninnorepinephrine reuptake inhibitors such as duloxetine and venlafaxine signicantly attenuate neuropathic pain. Indeed, duloxetine (Figure 6) is the newest approved medications for the treatment of the pain associated with diabetic neuropathy.59 Interestingly, in parallel to their preferred efcacy in the clinic, clinically used analgesics also have a differential analgesic prole in preclinical pain models (see Table 1). While opioid analgesics like morphine are potent and efcacious in all animal models of pain, including acute pain, pain associated with inammation in which they are particularly potent, and pain associated with neuropathy, NSAIDs such as ibuprofen and celecoxib are most potent and effective in animal models associated with inammation, with near to no efcacy in models of acute pain and neuropathic pain, and antiepileptics like lamotrigine and gabapentin are most potent and efcacious in animal models of neuropathic pain.
6.14.6
Unmet Medical Needs
Due to the relatively poor efcacy to tolerability ratio for opioid analgesics in treating neuropathic pain, this area represents a major unmet medical need. While gabapentin and other adjuvant analgesics have been reported to be clinically effective in treating neuropathic pain, the efcacy rates are relatively small and are often accompanied by side effects of sufcient magnitude to limit compliance.7 This situation is not surprising in that essentially all clinically used analgesic adjuvants were originally developed to treat other indications. Their clinical utility in treating pain has been based largely on clinical serendipity. In the case of inammatory or nociceptive pain, opioids provide signicant analgesic efcacy; however, long-term use of these analgesics is limited by both opioid-mediated side effects including constipation, and regulatory concern of opioid dependence and abuse liability. NSAIDs also provide moderate pain relief in these pain states, but are associated with GI disturbances. The COX-2 inhibitors represent an analgesic advance due to their enhanced GI safety prole; however, the long-term cardiovascular safety of these agents is controversial.
6.14.7
New Research Areas
The identication clinically useful analgesic targeting nonopioid mechanisms has been challenging as demonstrated by the failure of several novel tachykinin NK-1 receptor antagonists in clinical trials.39 Other novel analgesic agents have either not been advanced or are used in only limited conditions due to mechanism related toxicities. For example, the analgesic efcacy of ziconotide, a selective neuronal calcium channel (N-type, Cav2.2) blocker (discussed in more detail below) is limited to intrathecal administration in order to minimize severe cardiovascular adverse effects. Additionally, the development of several classes of adenosine kinase inhibitors as analgesics was halted due to the occurrence of vascular microhemorrhages in brain.60 Despite these difculties in translating advances in pain neurobiology into clinical useful analgesics, a number of novel analgesic mechanisms and compounds have been identied and validated in preclinical models. Some of these are described below.
6.14.7.1
Neuronal Nicotinic Receptor Agonists
Activation of neuronal nicotinic receptors (NNRs) represents a novel approach to pain management supported by the observation that epibatidine (isolated from Epipedobates tricolor) had signicantly greater analgesic potency than morphine in assays of acute thermal pain.61,62 While the mechanism of action of epibatidine was unknown, it was subsequently found to be a picomolar agonists at NNRs. NNR agonists with higher afnity for the a4b2 subunit (the predominant subtype in the CNS) relative to the a1b1dg nicotinic acetylcholine receptor subunit (located at the neuromuscular junction) had analgesic efcacy with a larger therapeutic window from severe side effects than did epibatidine.6367 These observations facilitated the discovery of ABT-594 (Figure 7), an a4b2-preferring NNR agonist that was synthesized independently of the identication of the mechanism of action of epibatidine. ABT-594 has broad-spectrum analgesic activity in both acute (hot plate, tail ick, formalin) inammatory (CFA), and neuropathic pain models. Importantly, ABT-594 showed less potential for analgesic tolerance than morphine in animal models and did not produce pharmacologic dependence.6365
6.14.7.2
Vanilloid Receptor Modulators
The analgesic actions of topically applied capsaicin, the active ingredient in hot chillies, has been known for many years; however, the clinical utility of vanilloid-derived analgesics has been limited by the initial burning sensation these
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Cl N O HN ABT-594
Figure 7 ABT-594, a neuronal nicotinic receptor (NNR) agonist.
O H N O Cl O O O SB-366791 H N O N F HN N H
F F
AMG 9810
Figure 8 Novel nonvanilloid TRPV1 receptor antagonists.
A-425619
compounds elicit. The cloning and characterization of the capsaicin-sensitive vanilloid receptor (TRPV1) has greatly enhanced understanding of the mechanism by which vanilloids, acid, and heat may alter nociceptor sensitivity.68 TRPV1 receptors are one member for a larger family of transient receptor potential (TRP) proteins, several member of which have been associated with sensory function including cold (TRPA1, TRPM8) and mechanical (TRPV3, TRPV4) sensitivity.68 These ndings have also led to the discovery of several distinct classes of TRPV1 antagonists (Figure 8).69,70 These compounds potently and selectively block capsaicin activation of TRPV1 in a competitive manner. Interestingly, these antagonists also effectively block TRPV1 activation by acid and heat, indicating that these agents may exert channel modulating activity as compared to direct channel activation. These latter effects may be species dependent with some capsaicin-competitive antagonists being ineffective in blocking acid activation of rat TRPV1 receptors. TRPV1 antagonists have demonstrated analgesic efcacy in animal models of inammatory pain, thus illustrating their potential to be clinically effective analgesics.
6.14.7.3
Excitatory Amino Acid Receptor Antagonists
The excitatory amino acid (EAA) glutamate functions as a primary excitatory neurotransmitter in the CNS, and activation of EAA-specic ionotropic and metabotropic receptor superfamilies in the spinal cord underlies the process of central sensitization involved in chronic pain.16 Activation of the heteromultimeric NMDA receptors (NR1/NR2B/ NR2D subunits) expressed in spinal cord contributes to the expression of tactile and thermal hyperalgesia. A number of competitive and noncompetitive NMDA receptor antagonists including (7)-CPP, MK-801, ketamine, and dextromethorphan (Figure 9) block hyperalgesia in animal models and attenuate the process of central sensitization.71,72 A problematic issue associated with NMDA receptor antagonists is their psychotomimetic effects that include both dysphoria and cognitive impairment. This has led to the search for ligands that are selective for specic NMDA channel subunits (e.g., NR2B) that may alter nociceptive processing with an improved therapeutic window relative to previous NMDA antagonists. CP-101,606 (Figure 9), a selective NR2B antagonist, effectively reduced pain in low back pain and spinal cord injury patients.73 Adverse events associated with CP-101,606 treatment were dizziness, and hypoesthesia, but were tolerated by the patients. Memantine (Figure 9) is a low-afnity (NR1/NR2B IC50 820 nM) noncompetitive NMDA antagonist that has analgesic efcacy in humans. In early clinical studies, memantine attenuated ongoing neuropathic pain symptoms in both diabetic and postherpetic neuralgia patients that memantine failed in Phase III pain indication trials.74 In addition to these agents, other NMDA antagonists are being investigated preclinically as potential analgesic. For example, MRZ-2/579 (Figure 9), a low-afnity noncompetitive NMDA antagonist, attenuates carrageenan-induced thermal hyperalgesia at doses that do not affect sensory-motor function.75 GV 196771A (Figure 9) modulates NMDA receptor function by blocking the glycine binding site of the NMDA receptor complex. Like memantine and dextromethorphan, GV 196771A produces antihyperalgesia in animal models at doses that do not elicit CNS side effects.76 Additionally, GV 196771A is only weakly active in cerebral stroke models suggesting differences in the physiological substrates of nociception and neuroprotection. NMDA receptor antagonists can provide opioid sparing effects and may prevent the
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Cl
H N
OH O
Cl N O
H2N CH3
N N N N H
COOH NH
CH3
Memantine
GV 196771A
LY 293558 CH3O
H3C H3C H3C
+ NH3
OH
CH3 CH3
OH N
H NCH3
HO CP-101,606 Dextromethorphan
MRZ-2/579
Figure 9 Antagonists for excitatory amino acid (glutamate) receptors.
tolerance related to prolonged opioid use. As noted above, late stage clinical trials of a dextromethorphan/morphine combination (MorphiDex) are ongoing. Antagonists of the kainic acid subtype of the glutamate receptor include LY 293558 (Figure 9) which was active in acute migraine.77
6.14.7.4
Calcium Channel Modulators
Modulation of N-type (Cav2.2) calcium channels has been shown to provide an avenue for development of novel analgesics, as exemplied by ziconotide, a 25 amino acid polycationic peptide originally isolated from the venom of a cone snail. Its delivery is limited to the epidural and intrathecal routes, as systemic administration has led to a risk for orthostatic hypotension.78 Ziconotide is approved for treating intractable cancer pain and chronic neuropathic pain. The clinical efcacy of ziconotide provides important validation of this novel analgesic mechanism. In addition to N-type calcium channels, T-type channels (Cav3.1 and Cav3.2) have also been implicated in nociceptive processing. T-type calcium channels are expressed on dorsal root ganglion neurons and intrathecal antisense treatment targeting the Cav3.2 subtype of T-type calcium channels effectively blocked all low-voltage calcium currents in dorsal root ganglion neurons and signicantly attenuated both acute and inammatory pain.79
6.14.7.5
Cannabinoids
Marijuana (cannabis) has been used to relieve pain for centuries.80 However, clinical evaluation of the major active cannabinoid, D9-tetrahydrocannabinol (D9-THC), has produced equivocal results in chronic cancer pain patients. Furthermore, the analgesic actions of D9-THC could not be clearly separated from the other well-described psychotropic actions of D9-THC. Investigation of the pharmacological actions of the cannabinoids has been greatly aided by the recent discovery of specic cannabinoid receptor subtypes (CB1 and CB2), elucidation of their signal transduction pathways, and the identication of putative endogenous ligands (e.g., anandamide).80 High densities of CB1 receptors are found in the CNS, while CB2 receptors are localized primarily to immune cells and peripheral nerve terminals. These advances in cannabinoid pharmacology suggest the possibility of identifying receptor subtype selective ligands. Cannabimimetics have been shown to produce antinociception in animal pain models via spinal and supraspinal actions on CB1 receptors, and by peripheral actions at CB2 receptors on sensory afferents and, indirectly, on immune cells. Recent compounds in preclinical development include agonists with improved oral bioavailability and/or enhanced receptor subtypes selectivity. CT-3 (Figure 10) is an orally active and nonselective analog of THC that dosedependently reduces acute nociception in the rat. Recently, CT-3 has been tested in the clinic in a phase II trial in chronic neuropathic pain patients and the results suggested that CT-3 could be useful in treating this condition.80 O-1057 (Figure 10) is a potent and moderately CB1 receptor selective analog of CT-3 that has improved water solubility and acute antinociceptive actions.67 HU-308 (Figure 10) is a novel, highly CB2 receptor selective agonist
343
CT-3 O-1057
R=H
O
R=
O N+ H CH2OH OCH3
HU-308
CO2H OR
O
O
O I
H3CO
Cl
O O
Cl
O N
O
N CH3 NO 2 N
OH O
O N
Steriochemistry
AM-1241
Figure 10 Agonists for cannabinoid receptors.
PRS-211375
GW405833
(Ki CB1410 mM, CB2 23 nM) that has antinociceptive effects in the persistent phase of the mouse formalin test, but was inactive in the acute phase of the formalin test.81 While no effects of HU-308 were observed on motor function, antinociceptive doses of the compound also reduced GI motility and blood pressure.82 More recently, the potential analgesic prole of CB2 agonists has been extensively characterized in in vivo pain models in rodents. PRS-211375 (Figure 10) has been shown to be CB2 selective (CB2 Ki 9 nM; CB1 Ki 300 nM) and a full agonist in adenylyl cyclase and GTPgS binding assays with similar potencies as observed in binding assays. PRS-211375 has good CNS penetration and has shown efcacy in various animal models including formalin, neuropathic pain models, acute thermal pain, visceral pain, and CFA-induced arthritis.83 PRS-211375 recently completed phase I clinical trial. AM-1241 (Figure 10) is another selective CB2 agonist used in preclinical models to identify the potential analgesic prole of CB2 agonists. This compound has been shown to decrease acute, inammatory, and neuropathic pain, its effects mediated through the release of b-endorphin and effects on opioid receptors.84 GW405833 (Figure 10), another CB2 agonist, has also been shown to produce analgesia in animal models of chronic pain including postoperative pain. However, contrary to the results obtained with AM-1241, the analgesic effects of GW405833 are not mediated through activity at opioid receptors.85
6.14.7.6
Sodium Channel Modulators
The activation of voltage-gated sodium channels is necessary for the generation of neuronal action potentials. A feature common to the local anesthetics and most analgesic adjuvants (e.g., carbamazepine, lamotrigine, and amitriptyline) is their ability to block sodium channels and this property may underlie the clinical utility of these agents in reducing pain. However, all of these agents possess other pharmacologically relevant activities that results in limits their analgesic effectiveness in the clinic. Notably, these include CNS sedation and/or untoward cardiovascular effects. The cloning and characterization of several sensory nerve-specic sodium channel subtypes has raised interest in the possibility of developing subtype-specic inhibitors which might overcome the cardiovascular and proconvulsant liabilities of nonselective agents. The voltage-gated sodium channel gene family consists of multiple members, termed Nav1.1 through Nav1.9.86 At least six of these channels are found in the peripheral nervous system.87 Structurally, the family has a high overall degree of similarity (around 50% identity), with subfamilies being very closely related (up to 90% identity). Susceptibility to blockade by natural toxins, particularly tetrodotoxin (TTX), has been typically used to classify sodium channel currents. Two TTX-resistant channels are present in the periphery: Nav1.8 (also called PN3 or SNS) and Nav1.9 (also called NaN). Nav1.8 is likely to be the more important sodium channel in regulating nociceptive signaling since in vivo antisense experiments targeting Nav1.9 did not reduce chronic neuropathic pain.88 Nav1.8 immunoreactivity is increased in the carrageenan inammatory pain model, and increased proximal to the site of nerve
344
injury in rats and humans. Antisense oligonucleotides against Nav1.8 prevented thermal hyperalgesia or mechanical allodynia from developing in animal models of neuropathic pain, and were also effective at reducing prostaglandininduced hyperalgesia. Nav1.8 knockout mice demonstrated a diminished response to noxious mechanical stimuli and delayed inammatory hyperalgesia. While the PN3/SNS subtype has been a major focus of research, other sodium channels may also be appealing targets for pharmaceutical intervention of pain.89,90 These data indicate that the development of antagonist that are selective for specic sodium channel subunits, like Nav1.8 may provide novel analgesic agents. The feasibility of this approach is likely to be difcult based on the poor selectivity of currently available sodium channel blockers, however, two NCEs have been recently described that show increased potency for tetrodotoxin-resistant sodium channels as compared to the typical analgesic adjuvants. Ralnamide (NW-1029) (Figure 11) inhibits TTX-resistant currents in rat dorsal root ganglion neurons with an IC50 value of 10 mM and dosedependently reduced allodynia in neuropathic pain models.91 CDA-54 (Figure 11) is a potent (IC50 B200 nM) nonselective sodium channel blocker that reduces pain in inammation pain models.92
6.14.7.7
Purines
6.14.7.7.1 P1 receptor agonists

The systemic or spinal administration of adenosine (ADO) or ADO A1 receptor selective agonists has been shown to provide clinically effective analgesia.93 However, analgesic efcacy of systemically administered ADO in neuropathic pain patients has been variable.94 In contrast, intrathecal injection of ADO or an A1 receptor agonist appears to consistently reduce pathological pain in neuropathic subjects or in healthy volunteers given intradermal capsaicin to induce central sensitization.9597 Despite these promising results, their profound effects on cardiovascular function have hampered the development of ADO receptors agonists as analgesics. Inhibition of the primary metabolic enzyme, adenosine kinase (AK), which regulates ADO availability enhances the benecial actions of adenosine at sites of tissue injury or trauma and AK inhibitors are potent antinociceptive and antiinammatory agents with an potentially improved therapeutic window over direct acting ADO receptor agonists.98 ABT-702 (Figure 12), a non-nucleoside AK inhibitor, has both analgesic (e.g., effective in acute nociception) and antihyperalgesic activity (e.g., effective in blocking both hyperalgesia and allodynia).98 The analgesic actions of ABT702 are blocked by selectivity ADO A1 receptor subtype antagonists and the locus of analgesic activity is in the spinal cord.98 ABT-702 also shows signicantly greater separation between its antihyperalgesic activity and its effects on CNS or cardiovascular function as compared to direct-acting ADO receptor agonists.
6.14.7.7.2 P2 receptor antagonists

The cloning and characterization of the family of ATP-sensitive ligand-gated ion channels (P2X receptors) provided mechanistic insights for the role of ATP as an extracellular signaling molecule.99 The P2X3 channel is localized
F O
HN O NH2
H2NO2S
N O O
H N OCF3
Ralfinamide
Figure 11 Novel voltage-gated sodium channel blockers.
CDA-54
Br NH2 N N N N ABT-702
Figure 12 ABT-702, a nonnucleoside adenosine kinase (AK) inhibitor.
N O
345
HO
OH O
HO N O O N N O N A-317491 A-740003 N N N O OMe OMe
Figure 13 A-317491 and A-740003, selective P2X3 and P2X7 ligand-gated ion channel antagonists, respectively.
primarily to sensory neurons, suggesting a role in pain transmission. The P2X3 messenger RNA (mRNA) occurs only in the trigeminal, dorsal root, and nodose ganglia, and the receptor is selectively expressed in sensory C-ber neurons that project to the periphery and spinal cord, and which are predominantly nociceptors. In addition, P2X3 receptors located presynaptically at the central terminals of primary afferent neurons may have a facilitatory role to enhance neurotransmission, leading to a further increase in pain sensation.100 A role of ATP in pain transmission is consistent with the observed induction of pain by ATP upon application to human skin, and with reports that intradermal and intrathecal application of ATP and ATP analogs (e.g., ab-methylene ATP (abmetATP)) into the rat hind paw evokes acute nociceptive behavioral responses. Transgenic disruption of P2X3 receptors in rodents via knockout, antisense, or short interfering RNA (siRNA) manipulations leads to decreased nociceptive sensitivity.101,102 A-317491 (Figure 13), a potent and selective antagonist of homomeric P2X3 and heteromeric P2X2/3 receptors that when given systemically and intrathecally dose-dependently reduces nociception in animal models of inammatory and neuropathic pain indicating that blockade of spinal P2X3 receptors may provide broad-spectrum analgesic effects in chronic pain states.100 P2Y2 receptors signal through protein kinase C (PKC) and, in turn, modulates the activation of TRPV1 receptors.103 Intrathecal antisense studies have also shown that P2X4 receptors acting via a spinal neuralmicroglial interaction alter nociceptive processing in neuropathic rodents.104 More recently, P2X7 receptor knockout mice have been characterized and show reduced inammation and neuropathic pain as compared to wild-type mice.105 P2X7 receptors are not localized on small-diameter neurons in the periphery, but are found on gial cells in the dorsal root ganglion.106 Blockade of P2X7 receptors leads to inhibition of IL-1b release from macrophages and glial cells, while antagonists like A-740003 are active in pain models.110 In addition, P2X7 receptors mediate the ability of ATP to stimulate glutamate release from glial cells, thus providing an additional mechanism for ATP-mediated fast neurotransmission.107
6.14.7.8
Emerging Pain Targets
As indicated above, a developing concept in pain research is the appreciation that neuroimmune interactions participate in nociceptive signaling in chronic pain states.25 This has greatly added to the potential list of candidate mechanisms that may offer an avenue for analgesic intervention. In addition to traditional mechanisms associated with neuronneuron communication, cytokines, chemokines, and inammatory acute phase proteins are now known to contribute to nociceptive signaling. This collection of potential analgesic mechanisms is further complemented by ndings that extracellular acid may also play a neuromodulatory role in the transmission of pain signals. Members of the TRP channel family are sensitive to both endogenous lipids as well as acidic pH.68,69 The activation of specic acidsensing ion channels (ASICs) also contributes to the encoding of noxious stimulation.108 The development of selective antagonists of ASIC3 antagonist A-317567 (Figure 14) provided the demonstration that this acid-sensing channel contributes to both inammatory hyperalgesia and pain associated with skin incision.108 As noted above, neurotrophic factors play important roles in the remodeling of the peripheral and central nervous systems in response to pain. Specically, nerve growth factor (NGF) is a neurotrophin that is an important survival factor for sensory neurons.109 However, NGF also has pronociceptive actions, producing pain and enhancing hyperalgesia in both experimental animals and in human clinical studies. The recent development of small-molecule antagonists like ALE0540 and PD90780 (Figure 15) as well as anti-NGF antibodies has enabled studies demonstrating that these agents effectively reduce chronic arthritic pain, skin incision pain, and tactile allodynia following peripheral nerve injury.109
346
N H2N
A-317567
NH2
Figure 14 A-317567, a selective antagonist of acid-sensing ion channels.
H O
N N
O O
O H N O N N N O OH
NO2 ALE 0540 PD 90780
Figure 15 Antagonists of nerve growth factor (NGF) binding to trkA and p75NTR.
6.14.8
Conclusions
The adverse physiological, psychological, and economic effects of inadequate pain management have become increasingly recognized in recent years. This has been accompanied by a growing awareness on the part of patients and caregivers that pain need not be tolerated, and an increased emphasis amongst physicians on the proactive treatment of pain. The unmet need for new analgesics remains substantial. Recent advances in the neurobiology of pain, together with the development of new preclinical and clinical pain paradigms, have revealed new opportunities for the development of analgesics, and raised the exciting possibility of entirely novel classes of analgesics in the future.
References
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. Merskey, H.; Bugduk, N. Classication of Chronic Pain, 2nd ed.; IASP Press: Seattle, WA, 1994. Harden, N.; Cohen, M. J. Pain Sympt. Mgmt. 2003, 25, S12S17. Elliott, A. M.; Smith, B. H.; Penny, K. I.; Smith, W. C.; Chambers, W. A. Lancet 1999, 354, 12481252. Ericksen, J.; Jensen, M. K.; Sjgren, P.; Ekholm, O.; Rasmussen, N. K. Pain 2003, 106, 221228. American living with pain survey; American Chronic Pain Association, Roper Public Affairs and Media: Rocklin, CA, 2004. Millan, M. J. Prog. Neurobiol. 1999, 57, 1164. Scholz, J.; Woolf, C. J. Nat. Neurosci. 2002, 5, 10621067. Cervero, F.; Laird, J. M. Pain 1996, 68, 1323. Woolf, C. J.; Costigan, M. Proc. Natl. Acad. Sci. USA 1999, 96, 77237730. Coda, B. A.; Bonica, J. J. In Bonicas Management of Pain, 3rd ed.; Lippincott: Baltimore, MD, 2001, pp 222240. Byers, M.; Bonica, J. J. In Bonicas Management of Pain, 3rd ed.; Lippincott: Baltimore, MD, 2001, pp 2672. Meyer, R. A.; Campbell, J. N.; Raja, S. N. Advances in Pain Research and Therapy; Raven: New York, 1985; Vol. 9, pp 5371. Abbott, J. D.; Moreland, L. W. Exp. Opin. Invest. Drugs 2004, 13, 10071018. Dworkin, R. H.; Backonja, M.; Rowbotham, M. C.; Allen, R. R.; Argoff, C. R.; Bennett, G. J.; Bushnell, M. C.; Farrar, J. T.; Galer, B. S.; Haythornthwaite, J. A. Arch. Neurol. 2003, 60, 15241534. Smith, P. A. Drug News Perspect. 2004, 17, 517. Woolf, C. J.; Mannion, R. J. Lancet 1999, 353, 19591964. Woolf, C. J.; Salter, M. W. Science 2000, 288, 17651768. Urban, M. O.; Gebhart, G. F. Proc. Natl. Acad. Sci. USA 1999, 96, 76877692. Treede, R. D.; Meyer, R. A.; Raja, S. N.; Campbell, J. N. Prog. Neurobiol. 1992, 38, 397421. McMahon, S. B.; Wall, P. D. Pain 1984, 19, 235247. Woolf, C. J. Nature 1983, 306, 686688. Woolf, C. J.; Thompson, S. W. Pain 1991, 44, 293299. Watkins, L. R.; Milligan, E. D.; Maier, S. F. Pain 2001, 93, 201205. Tsuda, M.; Inoue, K.; Salter, M. W. Trends Neurosci. 2005, 25, 101107. Honore, P.; Wade, C. L.; Zhong, C.; Harris, R. R.; Wu, C.; Ghayur, T.; Iwakura, Y.; Decker, M. W.; Sullivan, J. P.; Faltynek, C.; Jarvis, M. F. Behav. Brain Res. 2006, 167, 355364.
347
26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82.
Mogil, J. S.; Yu, L.; Basbaum, A. I. Annu. Rev. Neurosci. 2000, 23, 777811. Hargreaves, K.; Dubner, R.; Brown, F.; Flores, C.; Joris, J. Pain 1988, 32, 7788. Randall, L. O.; Selitto, J. J. Arch. Int. Pharmacodyn. Ther. 1957, 111, 409419. Chaplan, S. R.; Bach, F. W.; Pogrel, J. W.; Chung, J. M.; Yaksh, T. L. J. Neurosci. Methods 1994, 53, 5563. Dubuisson, D.; Dennis, S. G. Pain 1977, 4, 161174. Besson, J.-M.; Guilbaud, G. In The Arthritic Rat as a Model of Clinical Pain, Proceedings of the International Symposium, Saint-Paul de Vence, France, June 68, 1988; Besson, J.-M., Guilbaud, G., Eds.; Elsevier: Amsterdam, The Netherlands, 1988. Fernihough, J.; Gentry, C.; Malcangio, M.; Fox, A.; Rediske, J.; Pellas, T.; Kidd, B.; Bevan, S.; Winter, J. Pain 2004, 112, 8393. Ueda, H. Pharmacol. Ther. 2006, 109, 5777. Chacur, M.; Milligan, E. D.; Gazda, L. S.; Armstrong, C.; Wang, H.; Tracey, K. J.; Maier, S. F.; Watkins, L. R. Pain 2001, 94, 231244. Portenoy, R. K.; Lesage, P. Lancet 1999, 353, 16951700. Barden, J.; Edwards, J. E.; Mason, L.; McQuay, H. J.; Moore, R. A. Pain 2004, 109, 351356. Schuler, P. Pain Therapeutics, London, UK, 2005. Bostock, H.; Campero, M.; Serra, J.; Ochoa, J. L. Brain 2005, 128, 21542163. Boyce, S.; Hill, R. G. In Progress in Pain Research and Management; IASP Press: Seattle, WA, 1999; Vol. 16, pp 313324. Hill, R. Trends Pharmacol. Sci. 2000, 21, 244246. McQuay, H. Lancet 1999, 353, 22292232. Portenoy, R. K. Clin. Adv. Hematol. Oncol. 2005, 3, 3032. Wolfe, M. M.; Lichtenstein, D. R.; Singh, G. N. Engl. J. Med. 1999, 340, 18881899. Maxwell, S. R. J.; Webb, D. J. Lancet 2005, 365, 449451. McCleane, G. Exp. Opin. Pharmacother. 2004, 5, 12991312. Pasternak, G. W.; Letchworth, S. R. Curr. Opin. CPNS Invest. Drug. 1999, 1, 5464. Davis, M. P.; Walsh, D.; Lagman, R.; LeGrand, S. B. Lancet Oncol. 2005, 6, 696704. Davies, N. M.; Jamali, F. J. Pharmacol. Pharmaceut. Sci. 2004, 7, 332336. Hochberg, M. Am. J. Managed Care 2002, 8, S502S517. Hansson, P. T.; Dickenson, A. H. Pain 2005, 113, 251254. Williams, M.; Kowaluk, E. A.; Arneric, S. P. J. Med. Chem. 1999, 42, 14811500. Sawynok, J.; Reid, A. R.; Esser, M. J. Pain 1999, 80, 4555. Eisenach, J. C.; Gebhart, G. F. Anesthesiology 1995, 83, 10461054. Backonja, M.-M. Neurology 2002, 59, S14S17. Pappagallo, M. Clin. Ther. 2003, 25, 25062538. Dworkin, R. H.; Kirkpatrick, P. Nat. Rev. Drug Disc. 2005, 4, 455456. Belliotti, T. R.; Capiris, T.; Ekhato, I. V.; Kinsora, J. J.; Field, M. J.; Heffner, T. G.; Meltzer, L. T.; Schwarz, J. B.; Taylor, C. P.; Thorpe, A. J. et al. J. Med. Chem. 2005, 48, 22942307. Mortell, K. H.; Anderson, D. J.; Lynch, J. J.; Nelson, S. L.; Sarris, K.; McDonald, H.; Sabet, R.; Baker, S.; Honore, P.; Lee, C.-H. et al. Bioorg. Med. Chem. Lett. 2006, 16, 11381141. Waitekus, A. B.; Kirkpatrick, P. Nat. Rev. Drug Disc. 2004, 3, 907908. McGaraughty, S.; Cowart, M.; Jarvis, M. F.; Berman, R. Curr. Topics Med. Chem. 2005, 5, 4358. Qian, C.; Li, T.; Shen, I. Y.; Libertine-Garahan, L.; Eckman, J.; Biftu, T.; Ip, S. Eur. J. Pharmacol. 1993, 250, R13R14. Spande, T. F.; Garraffo, H. M.; Edwards, M. W.; Yeh, H. J. C.; Pannell, L.; Daly, J. W. J. Nat. Prod. 1992, 55, 707722. Bannon, A. W.; Decker, M. W.; Holladay, M. W.; Curzon, P.; Donnelly-Roberts, D.; Puttfarcken, P. S.; Bitner, R. S.; Diaz, A.; Dickenson, A. H.; Porsolt, R. D. et al. Science 1998, 279, 7781. Bannon, A. W.; Decker, M. W.; Kim, D. J. B.; Campbell, J. E.; Arneric, S. P. Brain Res. 1998, 801, 158163. Bannon, A. W.; Decker, M. W.; Curzon, P.; Buckley, M. J.; Kim, D. J. B.; Radek, R. J.; Lynch, J. K.; Wasicak, J. T.; Lin, N. H.; Arnold, W. H. et al. J. Pharmacol. Exp. Ther. 1998, 285, 787794. Barlocco, D.; Cignarella, G.; Tondi, D.; Vianello, P.; Villa, S.; Bartolini, A.; Ghelardini, C.; Galeotti, N.; Anderson, D. J.; Kuntzweiler, T. A. et al. J. Med. Chem. 1998, 41, 674681. Kesingland, A. C.; Gentry, C. T.; Panesar, M. S.; Bowes, M. A.; Vernier, J. M.; Cube, R.; Walker, K.; Urban, L. Pain 2000, 86, 113118. Caterina, M. J. Annu. Rev. Neurosci. 2001, 24, 487517. Honore, P.; Wismer, C. T.; Mikusa, J.; Zhu, C. Z.; Zhong, C.; Gauvin, D.; Gomtsyan, A.; El-Kouhen, R.; Lee, C.-H.; Marsh, K. et al. J. Pharmacol. Exp. Ther. 2005, 314, 410421. Swanson, D. M.; Dubin, A. E.; Shah, C.; Nasser, N.; Chang, L.; Dax, S. L.; Jetter, M.; Breitenbucher, J. G.; Liu, C.; Mazur, C. et al. J. Med. Chem. 2005, 48, 18571872. Herman, B. H.; Vocci, F.; Bridge, P. Neuropsychopharmacology 1995, 13, 269293. Kristensen, J. D.; Svensson, B.; Gordh, T. Pain 1992, 51, 249253. Sang, C. N.; Weaver, J. J.; Jinga, L.; Wouden, J.; Saltarelli, M. D. 2003 Abstract Viewer/Itinerary Planner, Program No. 814.9; Society for Neuroscience: Washington, DC, 2003. Sang, C. N.; Booher, S.; Gilron, I.; Parada, S.; Max, M. B. Anesthesiology 2002, 96, 10531061. Parsons, C. In New Developments in Glutamate Pharmacology; Orlando, FL, Mar 45, 1999. Quartaroli, M.; Fasdelli, N.; Bettelini, L.; Maraia, G.; Corsi, M. Eur. J. Pharmacol. 2001, 430, 219227. Sang, C. N.; Ramadan, N. M.; Wallihan, R. G.; Chappell, A. S.; Freitag, F. G.; Smith, T. R.; Silberstein, S. D.; Johnson, K. W.; Phebus, L. A.; Bleakman, D. et al. Cephalgia 2004, 24, 596602. Bowersox, S. S.; Gadbois, T.; Singh, T.; Pettus, M.; Wang, X. Y.; Luther, R. R. J. Pharmacol. Exp. Ther. 1996, 279, 12431249. `re, C.; Couette, B.; Poirot, P.; Pages, A.; McRory, J.; Snutch, T. P.; Eschalier, A. et al. EMBO J. 2005, Bourinet, E.; Alloui, A.; Monteil, A.; Barre 24, 315324. Grotenhermen, F. Curr. Drug Targets CNS Neurol. Disorders 2005, 4, 507530. Pertwee, R. G.; Gibson, T. M.; Stevenson, L. A.; Ross, R. A.; Banner, W. K.; Saha, B.; Razdan, R. K.; Martin, B. R. Br. J. Pharmacol. 2000, 129, 15771584. Hanus, L.; Breuer, A.; Tchilibon, S.; Shiloah, S.; Goldenberg, D.; Horowitz, M.; Pertwee, R. G.; Ross, R. A.; Mechoulam, R.; Fride, E. Proc. Natl. Acad. Sci. USA 1999, 96, 1422814233.
348
83. Meilin, S. B.; Bar-Joseph, A.; Reichstein, A.; Weksler, A.; Berkovich, Y.; Azulai, M.; Yacovan, A.; Amselem, S.; Nimrod, R.; David, P. 2005 Abstract Viewer/Itinerary Planner, Program No. 172.4; Society for Neuroscience: Washington, DC, 2005. 84. Ibrahim, M. M.; Porreca, F.; Lai, J.; Albrechy, P. J.; Rice, F.; Khodorova, A.; Davar, G.; Makriannis, A.; Vanderah, T. W.; Mata, H. P. et al. Proc. Natl. Acad. Sci. USA 2005, 102, 30933098. 85. Whiteside, G. T.; Gottshall, S. L.; Boulet, J. M.; Chaffer, S. M.; Harrison, J. E.; Pearson, M. S.; Turchin, P. L.; Mark, P. L.; Garrison, A. E.; Valenzano, K. J. Eur. J. Pharmacol. 2005, 258, 6572. 86. Goldin, A. L.; Barchi, R. L.; Caldwell, J. H.; Hofmann, F.; Howe, J. R.; Hunter, J. C.; Kallen, R. G.; Mandel, G.; Meisler, M. H.; Netter, Y. B. et al. Neuron 2000, 28, 365368. 87. Novakovic, S. D.; Eglen, R. M.; Hunter, J. C. Trends Neurosci. 2001, 24, 473478. 88. Porreca, F.; Lai, J.; Bian, D.; Wegert, S.; Ossipov, M. H.; Eglen, R. M.; Kassotakis, L.; Novakovic, S.; Rabert, D. K.; Sangameswaran, L.; Hunter, J. C. Proc. Natl. Acad. Sci. USA 1999, 96, 76407644. 89. Lai, J.; Porreca, F.; Hunter, J. C.; Gold, M. S. Annu. Rev. Pharmacol. Toxicol. 2004, 44, 371397. 90. Wood, J. N.; Boorman, J. Curr. Topics Med. Chem. 2005, 5, 529537. 91. Stummann, T. C.; Salvati, P.; Fariello, R. G.; Faravelli, L. Eur. J. Pharmacol. 2005, 510, 197208. 92. Brochu, R. M.; Dick, I. E.; Tarpley, J. W.; McGowan, E.; Gunner, D.; Herrington, J.; Shao, P. P.; Ok, D.; Li, C.; Parsons, W. H. et al. Mol. Pharmacol. 2005, 69, 823832. 93. Segerdahl, M.; Irestedt, L.; Sollevi, A. Acta. Anaesth. Scand. 1999, 40, 792797. 94. Eisenach, J. C.; Rauck, R. L.; Curry, R. Pain 2003, 105, 6570. 95. Karlsten, R.; Gordh, T., Jr. Anesth. Analg. 1995, 80, 844847. 96. Eisenach, J. C.; Curry, R.; Hood, D. D. Anesthesiology 2002, 97, 938942. 97. Eisenach, J. C.; Hood, D. D.; Curry, R. Anesthesiology 2002, 96, 2934. 98. Jarvis, M. F. Exp. Opin. Ther. Targets 2003, 7, 513522. 99. North, R. A. Physiol. Rev. 2002, 82, 10131067. 100. Jarvis, M. F.; Burgard, E. C.; McGaraughty, S.; Honore, P.; Lynch, K.; Brennan, T. J.; Subieta, A.; van Biesen, T.; Cartmell, J.; Bianchi, B. et al. Proc. Natl. Acad. Sci. USA 2002, 99, 1717917184. 101. Dorn, G.; Patel, S.; Wotherspoon, G.; Hemmings-Mieszczak, M.; Barclay, J.; Natt-Francois, J. C.; Martin, P.; Bevan, S.; Fox, A.; Ganju, P. et al. Nucleic Acids Res. 2004, 32, e49. 102. Honore, P.; Kage, K.; Mikusa, J.; Watt, A. T.; Johnston, J. F.; Wyatt, J. R.; Faltynek, C. R.; Jarvis, M. F.; Lynch, K. Pain 2002, 99, 1119. 103. Moriyama, T.; Iida, T.; Kobayashi, K.; Higashi, T.; Fukuoka, T.; Tsumura, H.; Leon, C.; Suzuki, N.; Inoue, K.; Gachet, C. et al. J. Neurosci. 2003, 23, 60586062. 104. Tsuda, M.; Shigemoto-Mogami, Y.; Koizumi, S.; Mizokoshi, A.; Kohsaka, S.; Salter, M. W.; Inoue, K. Nature 2003, 424, 778783. 105. Chessell, I. P.; Hatcher, J. P.; Bountra, C.; Michel, A. D.; Hughes, J. P.; Green, P.; Egerton, J.; Murn, M.; Richardson, J.; Peck, W. L. et al. Pain 2005, 114, 386396. 106. Zhang, X.-F.; Han, P.; Faltynek, C. R.; Jarvis, M. F.; Shieh, C.-C. Brain Res. 2005, 1052, 6370. 107. Donnelly Roberts, D. L.; Namovic, M. T.; Faltynek, C.; Jarvis, M. F. J. Pharmacol. Exp. Ther. 2004, 308, 10531061. 108. Dube, G. R.; Lehto, S. G.; Breese, N. M.; Baker, S. J.; Wang, X.; Matulenko, M. A.; Honore, P.; Stewart, A. O.; Moreland, R. B.; Brioni, J. D. Pain 2005, 117, 8896. 109. Hefti, F. F.; Rosenthal, A.; Walicke, P. A.; Wyatt, S.; Vergara, G.; Shelton, D. L.; Davies, A. M. Trends Pharmacol. Sci. 2006, 27, 8591. 110. Honore, P.; Donnelly-Roberts, D.; Namovic, M. T.; Hsieh, G.; Zhu, C. Z.; Mikusa, J. P.; Hernadez, G.; Zhong, C.; Gauvin, D. M.; Chandran, P. et al. J. Pharmacol. Exp. Ther. 2006, doi:10.1124/jpet.106.111559.
Biographies
Prisca Honore, PhD, a native of France, received a doctoral degree in molecular pharmacochemistry and experimental pharmacology from the University of Paris. Her postdoctoral training was completed at the University of Minnesota in Minneapolis, where she studied the role of substance P receptors expressing spinal cord neurons in pain transmission using an SP-Saporin toxin, in addition to investigating the mechanisms underlying bone cancer pain. Prisca joined Abbott Laboratories in 2000 and is a senior group leader in the Neuroscience Research division, at Abbott Park, IL. In 2004, she received the John C. Liebeskind Early Career Scholar Award from the American Pain Society.
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Michael F Jarvis, PhD, received his doctoral training in behavioral neuroscience at Rutgers University. He is currently a project leader and associate research fellow in Neuroscience Research, at Abbott Laboratories. A continuing research interest has been the study of the role of purines in modulating nociceptive signaling. His current research is focused on the identication and characterization of novel analgesic drug targets and ligands.
& 2007 Elsevier Ltd. All Rights Reserved No part of this publication may be reproduced, stored in any retrieval system or transmitted in any form by any means electronic, electrostatic, magnetic tape, mechanical, photocopying, recording or otherwise, without permission in writing from the publishers
Comprehensive Medicinal Chemistry II ISBN (set): 0-08-044513-6 ISBN (Volume 6) 0-08-044519-5; pp. 327349

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6.

14 Acute and Neuropathic Pain

Models of Nociceptive Pain

Models of Neuropathic Pain

6.14.4 6.14.4.1 6.14.5 6.14.5.1 6.14.5.2

6.14.6 6.14.7 6.14.7.1 6.14.7.2 6.14.7.3 6.14.7.4 6.14.7.5 6.14.7.6 6.14.7.7

6.14.7.8 6.14.8 References

Emerging Pain Targets Conclusions

Acute and Neuropathic Pain

Introduction: Pain States

Acute and Neuropathic Pain

Normal pain Brain Descending inhibitions Nociceptors

Pathophysiological pain Brain Descending Peripheral inhibitions sensitization Nociceptors

Ascending pain pathways

Ascending pain pathways

Central sensitization Spinal cord Spinal cord

Acute and Neuropathic Pain

Peripheral terminal primary afferent fiber

Dorsal root ganglion primary afferent cell body

SP CGRP TRPV1 ASICs

Nav1.8 TRPs P2X3

SP BDNF GAL NPY Nav1.3

Post synaptic neuron

Acute and Neuropathic Pain

Experimental Pain Models

Models of Acute Pain

6.14.3.1.1 Acute thermal pain

Acute and Neuropathic Pain

6.14.3.1.2 Acute mechanical pain

6.14.3.1.3 Acute chemical pain

Acute and Neuropathic Pain

Models of Nociceptive Pain

6.14.3.2.1 Adjuvant-induced arthritis

6.14.3.2.2 Unilateral inammation

6.14.3.2.3 Models of osteoarthritic pain

Acute and Neuropathic Pain

Models of Neuropathic Pain

6.14.3.3.1 Direct trauma to nerves

6.14.3.3.2 Inammation/neuritis/nerve compression

Peroneal Tibial Sural

Acute and Neuropathic Pain

6.14.3.3.4 Chemotherapy-induced neuropathic pain (vincristine/paclitaxel/platine)

Clinical Trial Issues

Acute and Neuropathic Pain

COOH Indomethacin Aspirin

O H3C N O N F F Celecoxib F Rofecoxib H3CO2S

N CH3 CH3 Amitriptyline

NH2 N NH2 N N Cl Cl S O NH CH3 Duloxetine

Acute and Neuropathic Pain

Neuropathic pain CFA

Translational Medicine in Pain

Acute and Neuropathic Pain

6.14.5.2.1 Nonsteroidal anti-inammatory drugs

Acute and Neuropathic Pain

6.14.5.2.2 Cyclooxygenase-2 inhibitors

Acute and Neuropathic Pain

Unmet Medical Needs

New Research Areas

Neuronal Nicotinic Receptor Agonists

Vanilloid Receptor Modulators

Acute and Neuropathic Pain

Excitatory Amino Acid Receptor Antagonists

Acute and Neuropathic Pain

H3C H3C H3C