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Multimo dal Pain

Ma nagement
in Veterinar y Me dicine :
The Physiolo gic Basis
of Pharmacolo gic
Leigh A. Lamont, DVM, MS
Multimodal analgesia  Nociception  Pain

Multimodal analgesia refers to the practice of combining multiple analgesic drug
classes or techniques to target different points along the pain pathway. This approach
has become widely accepted in veterinary medicine for two reasons. First, it takes
advantage of additive or synergistic analgesic effects that optimize analgesia and
improve patient comfort. Second, lower doses of individual analgesic agents are typically required, which reduces the potential for development of undesirable side
effects associated with treatment.
Although this strategy seems simple on the surface, effective multimodal pain management plans go beyond the philosophy that more drugs equal better analgesia.
A rational multimodal approach to treating pain must be based on an understanding
of physiology and pathophysiology. With this foundation, pharmacologic interventions
can be tailored to meet the needs of the patient. This article reviews the physiologic
basis of pain as it relates to analgesic treatments (Box 1) and also introduces new
developments in molecular biology that may guide analgesic drug development in
the future (Box 2).

Pain: a sensory event involving the peripheral and central nervous systems in
addition to an unpleasant experience arising from, and reciprocally affecting,
processes of higher consciousness

Department of Companion Animals, Atlantic Veterinary College, University of Prince Edward
Island, 550 University Avenue, Charlottetown, Prince Edward Island, Canada C1A 4P3
E-mail address:
Vet Clin Small Anim 38 (2008) 1173–1186
0195-5616/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.

by a nonnoxious stimulus) Hyperalgesia: increased pain response to a noxious stimulus at the site of injury (primary) or in surrounding undamaged tissue (secondary) . and modulation of signals generated by stimulation of peripheral nociceptors Noxious: a stimulus that damages or threatens to damage tissue. it may be mechanical. or thermal Allodynia: pain that is produced by a stimulus that does not normally provoke pain (ie. chemical.1174 Lamont Box 1 Analgesic drugs and their targets along the nociceptive pathway Drugs acting at peripheral nociceptors Capsaicin Local anesthetics Drugs acting at primary afferent fibers Local anesthetics a2-Agonists Drugs acting at the dorsal horn Opioids Nonsteroidal anti-inflammatory drugs (NSAIDs) a2-Agonists Local anesthetics Drugs acting at thalamocortical structures Opioids a2-Agonists Drugs acting at descending antinociceptive pathways Opioids a2-Agonists Drugs minimizing development of or showing efficacy during peripheral sensitization NSAIDs Opioids Drugs minimizing development of or showing efficacy during central sensitization Ketamine Amantadine Gabapentin Cyclooxygenase (COX)-2–specific NSAIDs Analgesia: the absence of pain sensation Nociception: the physiologic component of pain processing involving the transduction. transmission.

Thus. the stress system. and visceral tissues. notably. the perception of pain in human beings or domestic animals is much more complex than the sum of these nociceptive processes alone.8 antagonists Downregulation of Nav1. With this in mind. muscle. transduction of high-threshold (ie.1. the following sections outline these pathways. and cognitive brain functions. a basic understanding of these pathways remains a prerequisite for designing effective clinical pain management strategies. in addition to traditional sensory inputs. Peripheral Nociceptors In cutaneous tissues.Multimodal Pain Management in Veterinary Medicine Box 2 Potential targets for development of novel analgesic drugs Drugs acting at peripheral nociceptors Transient receptor potential (TRP) V1 antagonists TRPV1 desensitizers Drugs acting at primary afferent fibers Nav1. such as touch or pressure. Although there are certainly fundamental similarities between the pathways that produce pain and those that lead to other types of sensations. This complexity is exemplified in the chronic and neuropathic pain syndromes that continue to challenge our current understanding of pain. One such theory.’’ These neurosignature patterns may be triggered by sensory inputs but. this theory provides a template to explore factors that determine or modulate the body-self neuromatrix.8 activity by gene therapy Drugs minimizing development of peripheral sensitization Peripheral-acting opioids Bradykinin or protein kinase C (PKC) antagonists Nerve growth factor (NGF)–capturing drugs TrkA antagonists Drugs minimizing development of central sensitization Specific N-methyl-D-aspartate (NMDA) antagonists Glial antagonists or immunomodulators Cytokine or chemokine antagonists NOCICEPTION There is a tendency when discussing the physiology of pain to paint a simple stimulusresponse picture similar to that of the other somatosensations. requiring new theories to explain these phenomena better.2 states that the multidimensional experience we call pain is produced by characteristic neurosignature patterns of nerve impulses generated by a widely distributed neural network in the brain that he calls the ‘‘body-self neuromatrix. proposed by Melzack. noxious) stimuli into electrical impulses occurs at specialized free nerve endings 1175 . beginning in the periphery. although it is understood that a discussion of nociceptive pathways and acute pain is inherently limited in its ability to explain the complexities of the pain experience. including genetic influences. By recognizing that injury and pain may not always have a simple one-to-one relation. may also be generated independently of them.

and threshold of these nociceptor transducers constitute the first and most important filter in nociceptive processing and define the different classes of primary afferent fibers.7–9 All TRP receptors are considered to be primarily thermoreceptors. TRPV1 desensitization seems to depend on calcium and may be mediated by calmodulin. and one recent veterinary study has demonstrated that intrathecal administration of resiniferatoxin produced clinically significant analgesic effects in dogs with spontaneously occurring bone cancer. Resiniferatoxin is a capsaicin analogue. a member of the 2P-domain K1 channel family. TRPV3 and TRPV4.4 Most fibers are considered polymodal. Prolonged application of a topical preparation of capsaicin. such as the acid-sensing ion channels (ASICs).10 It is located on C and Ad fibers. and is also capsaicin-sensitive. with TRPM8 responding at <28  C and TRPA1 responding at <18  C.’’ the TRP ion channels have emerged as the major family involved in generating thermally and chemically evoked pain. the pharmaceutical industry is currently pursuing development of specific TRPV1 antagonists for potential use as clinical analgesics.5 Once they are activated. specificity. have been identified on nociceptive (Ad) and nonnociceptive (Ab fibers) and are involved in transducing mechanical and chemical stimuli.9 Analgesic Drugs Acting at Nociceptors At present. TRPV2. ultimately. TRPM. which initiates .9 The TREK-1 receptor is located on C and Ad fibers and responds to mechanical and thermal stimuli.6. responds to noxious heat (>42 C). an algogenic substance found in hot peppers. One exception is capsaicin. Other groups are looking at development of new synthetic capsaicin-like drugs to induce TRPV1 desensitization and produce analgesia. Within the TRP family are several subfamilies.7 Another type. capsaicin binds to TRPV1 receptors and activates them.14 There are commercial preparations of topical capsaicin available that have been used to treat human patients who have postherpetic neuralgia and other types of neuropathic pain. producing an inward current that depolarizes the membrane.3.3. whereas some are unimodal and respond to only one form of stimulus. is capsaicin-insensitive and has a higher thermal threshold (approximately 52 C).4.12 Another potentially important transducer is TREK-1. however. the most important member is TRPVI (also known as the vanilloid receptor-1). and TRPA. As mentioned previously. There has been considerable progress in the past decade in identifying the molecular structure and function of various nociceptor ion channels. Two additional TRPV members. Interestingly. responding to multiple types of noxious stimuli. TREK-1 receptors seem to be extensively colocalized with TRPV1 receptors in dorsal root ganglia neurons. there are few pharmacologic interventions that specifically target the process of transduction in the nonsensitized nociceptor. has been shown to desensitize TRPV1 and. Of all of these ‘‘transducers. chemical ligands. the channels open and Na1 and Ca21 ions flow into the nociceptor peripheral terminal.7 The TRPM and TRPA subfamilies have receptors that respond to cold. but they may also respond to mechanical and chemical activators.15 On the horizon for the future. or mechanical shearing forces.11. which initiates a pain response. including TRPV.1176 Lamont of certain primary afferent fibers known as nociceptors. In the TRPV subfamily. the transduction of noxious stimuli is manifested by influx of Na1 and K1 ions into the peripheral terminal of the nociceptor. other transducer channels.13 In addition. respond to lower thermal ranges and other chemical mediators.4 Most nociceptors are nonselective ion channels that are gated not by voltage but by temperature. to produce analgesia. Primary Afferent Fibers As discussed previously.6 The presence.

often referred to as ‘‘first pain. notably Nav1. and conduct impulses rapidly at a rate of 5 to 30 m/sec. They are small. however. Their principal effect in the nociceptive pathway is to inhibit nerve impulse conduction along Ad and C fibers. Another class of drugs. Type I and type II Ad fibers range in size from 1 to 5 mm in diameter.’’ which is the poorly localized. These afferents have small receptive fields and specific high-threshold ion channels that are activated by noxious thermal or mechanical input.3 These characteristics contribute to ‘‘second pain. gnawing sensation that persists after termination of the noxious stimulus. voltage-gated Na1 channels are activated. further depolarizing the membrane and causing a burst of action potentials. to inhibit nociceptive transmission. C fibers are polymodal and may be activated by thermal.Multimodal Pain Management in Veterinary Medicine depolarization. Ad and C fibers are still regarded as the principal nociceptive primary afferents. mechanical. in theory.’’ which is sharp. are classic Na1 channel blockers and are considered to be primary analgesic agents. thereby blocking the transmission of nociceptive signals to the central nervous system.5 to 2 m/sec. most of these channels are of the tetrodotoxin (TTX)-sensitive type. such as lidocaine.9 channels. which may subserve lowered threshold Na1 conductance. this channel has become a target for future drug development.7. and exposure to algogenic substances cause increased expression of a TTX-resistant (TTX-R) isoform. and have larger receptive fields compared with Ad fibers. Because of the restricted expression patterns of voltage-gated Na1 channels associated with nociceptive primary afferents. may also possess some ability to inhibit nerve impulse conduction when applied perineurally and may potentiate the intensity and duration of blockade when coadministered with a local anesthetic.3 C-fibers constitute most cutaneous nociceptive innervation. are myelinated. burning.8. including the nociceptor-specific Nav1.3. In addition to their cutaneous locations.18 Despite the clinical utility of the currently available Na1 channel blockers.5 mm in diameter. localized. There are several isoforms of Na1 channels that have been recognized for their specific role in nociception. and their differential activity is responsible for the unique sensory qualities of fast and slow pain. The conduction rate is correlated to the initial sensation of pain. Nav1. and thus have relatively narrow therapeutic indices. and the reader is referred elsewhere in this issue for a detailed discussion of their use.25 to 1. such as lidocaine and bupivacaine. or chemical stimuli. are unmyelinated with conduction velocities of only 0.8. Analgesic Drugs Acting at Primary Afferent Fibers The local anesthetics. block only fibers 1177 . neural insult. and transient.16 Isoform-specific channel antagonists or gene therapy approaches targeted at downregulating these specific isoforms could. ranging in size from 0. the a2-agonists. If the depolarizing current is of sufficient magnitude. however. C fibers are also found extensively throughout muscle and viscera.16 Under normal conditions. inflammation. Techniques like peripheral nerve blocks and epidural anesthesia are extremely effective components of a multimodal pain management plan.5. based on their expression of transductive receptors and TTX-R type Na1 channels. these drugs are all nonselective.5 These action potentials are conducted from the periphery to the central nervous system along the axons of primary afferent nociceptive fibers.17 It is now well recognized that multiple small-fiber afferents can transmit nociceptive impulses. Physicians and veterinarians exploit this class of drugs extensively by using them in local and regional nerve block techniques to prevent and actively manage pain. and Nav1.

the spinoreticular tract (SRT). whereas the motivational and affective aspects seem to be mediated by projections to the medial thalamocortical system. wide dynamic range (WDR) and nociceptive-specific (NS) neurons. with the SCT being of particular note in carnivores. and V. The primary synaptic transmitter present in all types of primary afferents is glutamate. remain among the most effective analgesics currently available. including nociceptive input. or with projection neurons that extend beyond the spinal cord to transmit nociceptive input to supraspinal structures. including the STT. Most of these neurons extend axons contralaterally to form the spinothalamic tract (STT). the a2-agonists have a similar mechanism of analgesic action within the dorsal horn. WDR neurons predominate in lamina V and receive innocuous input from lowthreshold Aa and Ab fibers in addition to nociceptive input from Ad and C fibers. the spinocervicothalamic tract (SCT). which inhibits nociceptive transmission.20 WDR neurons respond in a graded manner over large receptive fields and often receive convergent deep and visceral input.19 In addition to neurotransmitters. with propriospinal neurons.23 Analgesic Drugs Acting at the Dorsal Horn In the nonsensitized nervous system.and postsynaptic effects. IIa. and IIa. At the presynaptic level.21 Although there is considerable species variation in the relative importance of these tracts with regard to nociception.3 Primary afferents may synapse with local interneurons (which may be excitatory or inhibitory). Ad fibers terminate in laminae I. and the NSAIDs. . Dense populations of opioid receptors exist in the dorsal horn. from primary afferents. which also inhibits ascending nociceptive pathways. Most transmission between primary afferents and dorsal horn neurons occurs through postsynaptically located ionotropic a-amino-3-hydroxyl-5-methyl4-isoxazole propionic acid (AMPA) receptors with a small NMDA component. Dorsal Horn Neurons and Ascending Spinal Tracts The dorsal horn represents the first relay point for somatic sensory information. the principal analgesic drugs that act in the dorsal horn are the opioids. WDR and NS neurons project to the reticular formation and thalamus of the brain stem by way of multiple parallel pathways called tracts. II. and activation of these receptors may have pre. whereas C fibers terminate in laminae II. the spinomesencephalic tract (SMT). there is a long and growing list of other substances that can also modulate synaptic transmission in the dorsal horn. The opioids and the a2-agonists are used extensively in veterinary medicine to manage pain. There are two major types of nociceptive projection neurons located in the dorsal horn. the STT and SCT seem to be most important in domestic species. enhanced K1 efflux causes hyperpolarization of projection neurons. Because a2-adrenoceptors belong to the same superfamily as do opioid receptors. in particular. such as substance P. the sensory discriminative aspects of pain seem to be mediated by projections to the lateral thalamocortical system.20 Postsynaptically.22 In human beings. They have smaller receptive fields compared with WDR neurons and function in stimulus localization and discrimination. decreased Ca21 influx reduces the release of excitatory transmitter substances. Ad and C fibers enter the spinal cord by way of the dorsal roots of spinal nerves and synapse in specific laminae (layers) of the dorsal horn. en route to the brain.1178 Lamont transmitting pain input while leaving those transmitting innocuous sensations and motor and autonomic outputs intact. NS neurons are concentrated in lamina I and respond to input from Ad and C fibers only. the a2-agonists. and opioids. and the postsynaptic dorsal column pathway.

25 Of these. and after the procedure is completed. but that also includes spinal projections to the hypothalamus and amygdala. (3) the rostroventral medulla (RVM) and pons of the brain stem. have no primary analgesic activity. Analgesic Drugs Acting at Thalamocortical Structures Drugs like opioids and a2-agonists also have analgesic effects that are mediated at the supraspinal level through their effects on descending inhibitory nociceptive pathways. As such. efferent projections 1179 . and general anesthetics. cingulate. such as the anterior cingulate gyrus and prefrontal cortex. insular. on cells are excited by nociceptive input from the STT and engage parabrachial. may act to modify certain aspects of pain perception. The motivational and affective aspects of the pain experience arise in the medial thalamocortical system. Consequently. Despite the fact that an individual may be totally unaware of pain while under the influence of such drugs. upregulating it or downregulating it. it is universally recognized that patients undergoing painful procedures while under general anesthesia require a multimodal approach to pain management involving analgesic therapy before. the PAG has long been recognized as a key structure in the endogenous analgesia system. phenothiazines. Afferent input from the STT. which includes relay nuclei in the medial thalamus that send projections to limbic structures. completely obliterate the perception of pain. although not producing analgesia. there are unique populations of cells referred to as ‘‘on’’ and ‘‘off’’ cells. At the level of the midbrain. and thus are also considered to have central-acting analgesic effects.24. it is equally important to recognize that there are powerful descending pathways that are able to modulate the pain response. the role of most of these agents is to suppress or inhibit the development of central sensitization rather than to induce analgesia in the nonsensitized state. the PAG and the RVM are generally viewed as the core of this important system. are critical in producing hyperalgesia after peripheral tissue injury by maintaining central sensitization. Descending Antinociceptive Pathways In addition to the ascending nociceptive pathways outlined previously. Other drug classes. (2) the periaqueductal gray matter (PAG) of the midbrain.27 These cells. such as benzodiazepines. They are able to decrease or. Within the RVM. In addition. and septohippocampal pathways subserving arousal and aversive reactions to pain. Thalamocortical System As mentioned previously. hypothalamic. This system has four different tiers: (1) the dorsal horn. the sensory discriminative aspects of pain are produced in the lateral thalamocortical system.26 Predictably. nociceptive processing continues virtually unabated during this time. it now seems. they also inhibit cyclooxygenase (COX) within the spinal cord dorsal horn.Multimodal Pain Management in Veterinary Medicine The NSAIDs are also widely used in veterinary medicine to manage various types of pain. and (4) thalamocortical structures.3. in the case of general anesthetics. Although there are numerous other drugs that may have an impact on dorsal horn modulation of nociceptive input. off cells hyperpolarize in response to STT activation and reduce the transmission of nociceptive volleys in the brain stem. during. the sedative effects induced by these drugs. Although their peripheral antiprostaglandin effects make them obvious choices for minimizing development of peripheral sensitization of nociceptors.3 Conversely. which consists of relay nuclei in the lateral thalamus and the primary and secondary somatosensory cortices. however. these agents are discussed in a later section. by altering the state of consciousness.

and nociception-containing neurons of the PAG.29 NERVOUS SYSTEM SENSITIZATION In the clinical setting. thus. The a2-agonists bind receptors in a group of catecholaminergic nuclei in the pons known as the locus ceruleus (LC).5 Inflammatory mediators may be broadly classified into two categories: direct or indirect acting. actually modify nociceptor threshold and kinetics. Opioids from the PAG act postsynaptically to suppress GABAergic interneurons in the brain stem. by means of phosphorylating receptors and ion channels within the terminal. and cytokines. increased sensitivity to noxious stimuli (hyperalgesia). such as ATP and K1 ions. If a noxious stimulus is sufficiently intense to produce such injury. which receives noradrenergic efferents from the PAG and also extends noradrenergic axons to the spinal cord. Peripheral Sensitization Injury to tissues causes inflammation that results in profound changes to the chemical environment of nociceptor peripheral terminals. These clinical findings are a result of changes in nervous system processing occurring peripherally and centrally. analgesia may also be mediated at the supraspinal level through descending antinociceptive pathways. Of the direct-acting mediators.28. local pH decreases.30 Many of these chemicals act on G-protein–coupled receptors or tyrosine kinase (TrK) receptors expressed on nociceptor terminals. physicians and veterinarians are often called on to manage pain associated with substantial tissue injury. can cause changes in TRPV1 by means of activation of cyclic adenosine monophosphate (cAMP)–dependent protein kinase A (PKA) . some are considered nociceptor activators because they directly stimulate the nociceptor. Damaged cells release their intracellular contents. and pain after innocuous stimuli (allodynia). Despite the potential for adverse side effects associated with their administration. enkephalin. which. a few selected mediators are presented. Prostaglandin E2 (PGE2). prolonged poststimulus sensory disturbances may be observed. physicians and veterinarians continue to use exogenous opioids extensively because they remain among the most powerful and efficacious analgesics available. instead. Although the analgesic effects of the a2-agonists have traditionally been attributed to their effects at the level of the spinal cord.5 A discussion of all the relevant inflammatory mediators that play a part in peripheral sensitization is beyond the scope of this article.3 Analgesic Drugs Acting at Descending Antinociceptive Pathways Obviously. Activation in the LC seems to contribute indirectly to analgesia at the level of the dorsal horn through these descending projections. and nuclei of the limbic forebrain and hypothalamus all activate endorphin-.1180 Lamont from the cingulate gyrus. the opioids are the class of drugs that play the most significant and best known role in descending nociceptive modulatory pathways through their actions at multiple levels. thereby disinhibiting tonic and burst activity of descending serotonergic and adrenergic bulbospinal pathways. Intracellular signaling pathways are then activated.27 Projections extending from the PAG to the brain stem are inhibitory and excitatory. for example. chemokines. including the PAG and the dorsal horn. making it hyperresponsive to subsequent inputs. including continued pain. whereas others are nociceptor sensitizers because they sensitize the terminal. Prostaglandins are considered the prototypic nociceptor sensitizers. and growth factors are produced by inflammatory cells that are recruited to the site of damage.

34 The receptor tyrosine kinase known as TrkA and the receptor p75 NTR bind NGF. As its contribution to the pain response continues to be unraveled. however. was thought to be regulation of neuronal survival in the developing nervous system.36 Finally. lipoxygenase (LOX). are the classic group of drugs with efficacy at inhibiting peripheral sensitization.38 Analgesic Drugs that Inhibit Peripheral Sensitization The NSAIDs. the TRPV1 channel. First. which would offer the possibility of analgesia without centrally mediated adverse side effects. the TRPV1 receptor seems to be responsible for most bradykinin-induced nociceptive activity. it seems that NGF may soon be recognized primarily for its role as a pain mediator. resulting in phosphorylation of TRPV1 and radically lowering its thermal threshold (from approximately 42 C to 35 C). which includes brain-derived neurotrophic factor (BDNF). NGF can sensitize TRPV1 channels directly through PKC signaling. such as bradykinin and NGF. and elevated levels are sustained throughout chronic inflammation. although evidence has emerged over the past decade suggesting that these drugs have peripheral effects as well. the role of neurotrophic factors. Because they focus on COX pathways only. Increased levels of NGF may contribute to peripheral sensitization directly or indirectly. NGF released under conditions of tissue injury and inflammation can also sensitize nociceptors indirectly by activating mast cells.Multimodal Pain Management in Veterinary Medicine and Ca21-dependent protein kinase C (PKC). 1181 . Second. Opioid receptors of all three major types have been identified on the processes of sensory neurons. NGF is the founding member of the neurotrophin family of proteins. retrograde NGF signaling from nociceptor peripheral terminals triggers altered gene expression in the cell bodies to produce substance P. the ASIC3 channel. These proteins further sensitize the primary afferents and contribute to the phenomenon of primary hyperalgesia. and they respond to peripherally applied opioids and locally released endogenous opioid peptides when upregulated during inflammation.40 Currently available opioid analgesics bind central and peripheral opioid receptors nonselectively. the currently available NSAIDs always have a ceiling effect that limits their analgesic potential. NSAIDs are widely used in veterinary medicine for the management of acute perioperative pain and various types of chronic pain. including phospholipase C (PLC). bradykinin can also activate TRPA1 in a PLC-dependent manner to enhance noxious cold sensitivity.33 In addition to its ability to reduce TRPV1 thermal thresholds dramatically. PKC. Thus. numerous other sensitizers. Like PGE2.8 channel. such as NGF. and BDNF. there is the theoretic potential to develop selective ligands for peripheral opioid receptors. are still able to alter nociceptor function significantly during tissue injury and inflammation. neurotropin 3 (NT-3). however. phospholipase A (PLA).5.32 Bradykinin seems to work through multiple signaling pathways to reduce TRPV1 thermal thresholds.36 Evidence indicates that TrkA receptors are mandatory for the nociceptive actions of NGF but that p75 NTR may also play a role.31 Bradykinin is an example of a direct-acting mediator capable of nociceptor activation and sensitization.35. downstream of this. Opioids have traditionally been considered the prototype class of centrally acting analgesics. and. the Nav1. through their antiprostaglandin effects. Traditionally. and neurotropin 4 (NT-4).39.37 Induction of expression of NGF is an early event in injured and inflamed tissues.11 A relatively new discovery is the importance of neurotrophic factors as key players in the process of peripheral sensitization.35.

PKC). considerable evidence has accrued to support the notion that glial cells are in fact key players in the creation and maintenance of pathologic pain states.41 Within seconds of major nociceptive inputs.5 Later. thereby favoring the open-state configuration. central sensitization is considered to depend on activity.1182 Lamont Other future drug discovery approaches to inhibit peripheral sensitization include the following: (1) drugs that reduce bradykinin production. now elicit pain (called tactile allodynia). including substance P and BDNF.46 It is now clear that glial cells regulate morphine analgesia. . One key receptor involved in these changes is the glutamate-activated NMDA receptor. tumor necrosis factor-a (TNFa).45.34 Central Sensitization In the same way that the peripheral terminal of the nociceptor can become sensitized. (4) drugs that prevent NGF binding to TrkA. do not respond to noxious inputs are recruited and contribute to the pain response. numerous intracellular signaling pathways are activated in the dorsal horn by the neurotransmitter glutamate in addition to other neuromodulators. it is triggered by nociceptor input into the spinal cord. and IL-6. many of the alterations underlying central sensitization are similar to those that produce peripheral sensitization. such as macrophage inflammatory protein-2 and monocyte chemoattractant protein-1.44 Important proinflammatory cytokines include interleukin (IL)-1b.32. Increased synaptic efficacy seems to result from two primary mechanisms: (1) alterations in ion channel or receptor activity arising from posttranslational processing and (2) mobilization of receptors to neuronal membranes. under normal circumstances. such as a light touch to the skin. which results in the production of numerous proinflammatory mediators. (3) NGF-capturing drugs that could effectively remove free NGF. Mechanistically.44 Chemokines (ie.43 Together.5 Recent investigations into the basis of central sensitization have revealed the central neuroimmune response as a driving force. dorsal horn nociceptive neurons can also exhibit increased excitability. Furthermore. In general.43.42 Traditionally. recruit macrophages and neutrophils from the circulation into nerves. tolerance.43 Glial cell activation occurs secondary to nerve trauma or inflammation. and dependence and withdrawal. chemoattractant cytokines). Phosphorylation of this receptor stimulates its mobilization from intracellular stores to the synaptic membrane and increases its responsiveness to glutamate by removal of the voltage-dependent Mg21 ion block. Initially. and (5) drugs that inhibit TrkA signaling. these neuroexcitatory substances released after glial cell activation can create and maintain the state of augmented pain facilitation known as central sensitization. it is sustained beyond the initiating stimulus by transcriptional changes in the molecular machinery of the cell and is referred to as transcription dependent. these immune cells also seem to compromise opioid efficacy for management of clinical pain. it is as yet unknown how pervasive this glial regulation may turn out to be. nonneuronal glial cells were thought to function mainly as ‘‘housekeepers.47 Although it is also clear that such effects are not limited to morphine. dorsal horn neurons begin to exhibit hyperresponsiveness and the ensuing clinical manifestations become evident. Within the past decade. (2) drugs that block binding of bradykinin or one or more of its signaling pathways (eg. Exaggerated pain responses are noted within the injured area (called primary hyperalgesia) and also well outside the site of injury (called secondary hyperalgesia). As well. with particular relevance in chronic pain states after peripheral nerve injury.’’ whose role was to provide support and nutrition to neurons while acting as passive bystanders of neuronal transmission. that is. This means that normally innocuous stimuli. low-threshold Ab fibers that.

they suggest that pain syndromes should be reclassified and treated based on their inflammatory profiles. or drugs with anticytokine or antichemokine effects. inhibition of this receptor is a rational analgesic strategy.54 Thus.52.54 The resultant COX-2–mediated increase in PGE2 production contributes to a late-onset. 1183 . and (4) modulation of neuronal transmission. Ketamine has NMDA antagonistic properties and is a drug well known to veterinary medicine. as discussed previously. wherein it has been used traditionally as a short-acting anesthetic. a transition to mechanism-specific pharmacologic management of pain seems to be the way of the future. Such agents have significant potential to reduce opioid tolerance and improve analgesic efficacy in chronic neuropathic pain states. (3) inhibition or suppression of neuronal afferent and efferent (motor) transmission. Whether this theory proves to be true or not. as novel analgesic agents.51 The intensity of the analgesic effect achieved with gabapentin seems to be proportional to the magnitude of sensitization within the dorsal horn. Evidence suggests that this drug works by binding to the a2-d1 subunit of presynaptic voltage-gated calcium channels that are upregulated during central sensitization. Specifically. COX-2–specific NSAIDs are likely to continue to be important components of multimodal pain management strategies because of their ability to dampen central sensitization. and diffuse phase of central sensitization. The new appreciation of the importance of immune glial cells in the pain response is currently driving the search for antiglial drugs. (2) inhibition or suppression of production of the appropriate inflammatory mediators. Ketamine has been shown to reduce the early phase of central sensitization and the resultant hypersensitivity to pain. have effects at numerous locations along nociceptive pathways.53 The NSAIDs.56 This theory is appealing in that it supports development of rational multimodal analgesic strategies tailored to the individual patient rather than empiric trial-and-error approaches.55. because of the widespread distribution of the NMDA receptor throughout the brain. peripherally and centrally. they recommend following four general principles for the treatment of all types of pain: (1) determination of the inflammatory profile of the pain syndrome. which limits its clinical utility. NEW DIRECTIONS IN UNDERSTANDING THE BIOCHEMICAL BASIS OF PAIN A group of investigators has recently proposed an interesting theory that the origin of all pain is inflammation and the inflammatory response.48.55 Furthermore. prolonged. Because amantadine’s predominant inhibitory mechanism is stabilization of NMDA channels in the closed state50 rather than blockade of current flow through open channels like ketamine. Development of new anti-NMDA drugs that are able to block central sensitization without other central nervous system side effects is being actively pursued at this time.Multimodal Pain Management in Veterinary Medicine Analgesic Drugs that Inhibit Central Sensitization Because of the importance of the NMDA receptor in central sensitization.49 Unfortunately. COX-2 begins to be expressed by neurons in many areas of the central nervous system several hours after localized peripheral tissue injury. psychomimetic side effects may accompany ketamine’s analgesic effects. amantadine seems to have a more favorable clinical safety profile. Amantadine is another drug with anti-NMDA effects that has been shown to produce analgesia. The anticonvulsant gabapentin is another drug used increasingly by veterinarians as an adjunctive and occasionally primary analgesic agent.

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