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Mechanisms of pain and their therapeutic implications

William W. Muir III, DVM, PhD, DACVA, DACVECC, and Clifford J. Woolf, MD, PhD

ain is an everyday occurrence for humans and other animals, helping to protect against injury, but for some it is also a continuous relentless crippling sensory experience that causes suffering and distress. Traditionally considered a sign of pathologic changes or disease and valued primarily as a diagnostic tool, pain is presently recognized as being able to induce severe stress and profound effects on animal behavior, constitution, and physiology, in conjunction with or independent of other diseases.1-3 Many animals are inadequately treated for pain. Veterinarians may not provide optimal analgesic therapy because of lack of familiarity with current therapeutic strategies, concerns regarding the potential for the development of drug-induced adverse effects (eg, anorexia and signs of depression) or toxicity (eg, gastric ulcers and liver or renal failure), and the need to comply with federally mandated regulations. Furthermore, pain may be considered to be temporary, secondary to a primary disease, or, if treated, may impose an economic burden (eg, swine castration). Comprehensive clinical data regarding the incidence, prevalence, and severity of pain in animals with naturally occurring diseases are quite sparse, making it difficult to identify target groups, prescribe or evaluate therapies, or provide guidelines for the optimization of wellness programs. The lack of validated diagnostic techniques and pain scoring systems that could be used to evaluate pain and determine the clinical efficacy of veterinary-approved drugs only magnifies the problem.4-9 The physiologic, behavioral, and ethical consequences of inadequate pain therapy in veterinary patients are important.10-12 Development and use of species-specific pain scoring systems would greatly facilitate evaluation of pain in veterinary patients and has, for the first time, been validated for routine assessment and pain management in rats.13 The approach uses objective behavioral analysis software that analyzes the frequency and duration of the animals position, posture, and specific activity within a confined space. This analysis in conjunction with select speciesspecific behaviors has promise for estimating the sever-

ity of pain and hopefully may be modified for clinical use in domesticated species. Development of an evaluative system for severity of pain and the known mechanisms responsible for pain would facilitate comparison of research with clinical observations, suggest alternate diagnostic techniques, and permit a more comprehensive evaluation of various clinical analgesic therapies. Increased knowledge, changing attitudes, and greater emphasis on animal welfare have increased the desire to treat pain in private veterinary practice. The purpose of this review of pain was to define terms, describe key concepts, and highlight the important mechanisms responsible for pain, thereby providing a perspective for present and future therapies Types of Pain Pain is a perceptual experience that is commonly associated with tissue-damaging stimuli (Fig 1). Pain induces stress that, when severe (ie, distress), may threaten the animals well-being.3 Acute pain serves a protective role by enabling healing and tissue repair, but intense unrelenting chronic pain has little or no protective value. Chronic pain induces biochemical and phenotypic changes in the nervous system that escalate and alter sensory inputs, resulting in physiologic, metabolic, and immunologic alterations that threaten homeostasis and contribute to illness and death.10 The International Association for the Study of Pain has defined pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage and recently added that the inability to communicate in no way negates the possibility that an individual is experiencing pain and is in need of appropriate pain relieving treatment.14 This definition links sensory experiences with actual or potential tissue damage and implies that just because the patient doesnt talk or is incapacitated to the point that they cannot respond doesnt mean that they are not experiencing pain and do not require therapy. It also recognizes the importance of an unpleasant emotional experience (eg, fear) in triggering homeostatic responses similar to those induced by noxious stimuli. Noxious stimuli elicit reflex withdrawal, behavioral, autonomic nervous system, neuroendocrine, and immune system responses in proportion to the severity of the noxious stimulus.3,10,12 Nociception is the detection of a noxious stimulus and the transmission of that information to
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From the Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210-1089 (Muir); and Neural Plasticity Research Group, Department of Anesthesia & Critical Care, Harvard Medical School, Massachusetts General Hospital, Boston, MA 02129-2000 (Woolf). 1346 Vet Med Today: Reference Point

Figure 1Schematic diagram of the pathways and physiologic processes involved in pain sensation, including stimulus transduction, transmission, modulation, projection, and perception. Importantly, inhibitory signals from the brain (not shown) modify sensory input to the dorsal horn of the spinal cord.

the brain. Pain is the perception of the sensual experience induced by a noxious stimulus. Induction of pain involves the activation, modulation, and modification of primary sensory and central neurons. Nociceptive pain, also called physiologic pain, occurs when a stimulus that induces minimal or no tissue damage activates high-threshold sensory nerve fibers, warning the organism of potentially tissue damaging events. Physiologic pain is well localized, transient, and plays a vital role in the bodys normal defense mechanisms by initiating protective reflex, physiologic, and avoidance responses (Fig 2).15-17 Clinical pain, by contrast, occurs when excessively intense or prolonged stimuli induce tissue damage that results in extended discomfort and abnormal sensitivity. Clinical pain may arise spontaneously and is characterized by a low threshold to noxious stimuli (ie, hypersensitivity), an exaggerated response to noxious stimuli (hyperalgesia), and pain at the site (primary hyperalgesia) and beyond the area of primary tissue or nerve injury into surrounding uninjured tissue (secondary hyperalgesia and extraterritorial pain). Clinical pain is caused by inflammation associated with tissue damage (inflammatory pain) or central or peripheral nerve injury (neuropathic pain) and may be induced by normally innocuous stimuli (allodynia). Surgical procedures (eg, castration, declaw), trauma (eg, lacerations, fractures), ischemia (eg, thromboembolism, intestinal strangulation), osteoarthritis, laminitis, infection, and abscessation are causes for inflammatory pain, whereas nerve transection and compression are causes for neuropathic pain. Head trauma, vertebral disc prolapse, some operative procedures (eg, amputation, total ear canal ablation), cancer, and some localized inflammatory processes (eg, pancreatitis, laminitis) are likely to involve elements of both inflammatory and neuropathic pain. Peripheral sensitization, a reduction in the threshold to painful stimulation on exposure of the nerve terminal to sensitizing agents, is caused by inflammation at the site of tissue damage or
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trauma and may be augmented by sympathetic nervous system interactions with primary sensory afferents.17,18 Central sensitization, an activity-dependent increase in spinal neuron excitability that enables a response to normally ineffective inputs, is responsible for secondary hyperalgesia.17,19 Intense or prolonged noxious stimulation may cause alterations in patterns of gene expression, altering the phenotype of each neuron and providing the nervous system with a substantial degree of neuroplasticity.20 Importantly, hyperalgesia and allodynia may be as much a function of changes in gene expression as they are an expression of increases in excitability in peripheral and spinal cord neurons. Neurobiology of Sensory Nerves One of the most important functions of the nervous system is to warn animals of potential tissue damage. Sensory nerves serve this role.21-24 Sensory nerves are composed of 2 distinct classes of cells, glial (glue) cells and nerve cells (neurons). Glial cells nourish and support nerve cells.24 Neurons sense and conduct sensory information.24 The cell bodies of peripheral sensory nerves are located in the dorsal root ganglia of the dorsal root of the spinal nerves for nerves originating in the body (Fig 1) or in the trigeminal ganglia for nerves transmitting sensory information from the head (trigeminal, facial, glossopharyngeal, and vagus nerves). Classification of sensory neuronsSensory nerve fibers are classified into 3 groups on the basis of function, anatomy (myelination), and the speed with which they conduct electrical impulses.21 Large myelinated group A sensory nerve fibers are activated by lowintensity stimuli (ie, they have low threshold) and normally conduct non-noxious information (touch, vibration, pressure, and limb movement) rapidly (conduction speed, 30 to 70 m/s). These neurons receive input from specialized encapsulated receptors located at the terminal peripheral ends of their dendrites. Smaller lightly myelinated A and nonmyelinated C sensory
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Figure 2Schematic diagram of the structures and processes involved in physiologic pain. Minimal or nontissue-damaging stimuli are transduced by thermal, mechanical, and chemical peripheral nociceptors and transmitted to the dorsal horn of the spinal cord by A and C fibers that release glutamate, activating dorsal horn neuron receptors that mediate reflex responses and transient pain. A, A, C = Sensory nerve fibers. VR1 = Vanilloid (heat) receptor. mDEG/BNaC = Degenerin/epithelial (mechanical) sodium channel. P2X3 = Purine (chemical) receptor. TTXr = Tetrodotoxin resistant sodium channel. = Mu opioid receptor. = Delta opioid receptor. 2 = Alpha-2 receptor. GABA- = Gamma amino butyric acid- receptor. TrkB = Tyrosine kinase B receptor. VGCC = Voltage gated calcium channel. NMDA = N-methyl-D-aspartate receptor. AMPA/KAI = -Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate receptors. mGluR = Metabotropic glutamate receptor. NSC = Nonspecific cation channels. NK1= Neurokinin receptor.

nerve fibers are predominantly (> 90%) high-threshold and transmit noxious stimuli at much slower rates (A, 2.5 to 30 m/s; C, < 2.5 m/s).24 Transduction and transmissionPain occurs when high-threshold transducers located on the distal terminals of A and C nociceptors are activated (Fig 2).22,23 Most nociceptors are polymodal and respond to multiple forms of noxious stimulation (eg, thermal, mechanical, chemical, or electrical), although some are unimodal and respond only to thermal or mechanical stimuli.23 Nociceptors encode the intensity, duration, location, and quality of the noxious stimulus and, once activated, transduce noxious stimuli into depolarizing electrical potentials (action potentials) that are transmitted to the spinal cord where they are modified (ie, modulated) before being relayed (ie, projected) to the brain for final processing (ie, perception). Types of C fibersThe C fibers have been divided into 2 relatively distinct groups on the basis of peptide content and site of termination in the spinal cord.23,25 Some C fibers express adenosine- and adeno1348 Vet Med Today: Reference Point

sine triphosphate (ATP)-sensitive receptors (eg, P2X3) and glial cell-derived neurotrophic factor receptors and bind the lectin IB-4, whereas others synthesize the peptides substance P and calcitonin gene related peptide (CGRP) and the nerve growth factor (NGF) receptor tyrosine kinase A.26 Activation of P2X3 (purinergic) receptors by ATP released from damaged nerves causes hyperalgesia. Both groups of C fibers express the capsaicin-sensitive vanilloid receptor VR1 (capsaicin is the hot [spicy] ingredient in chili peppers).26 The VR1 receptor is a ligand-gated nonselective cation channel that responds to protons (H+).27 The VR1 receptors transduce noxious heat stimuli, purine receptors (eg, P2X3) transduce chemical stimuli, and members of the degenerin-epithelial sodium channel (mDEG) family, specifically brain sodium channel (BNaC) subunits, presently known as acid-sensing ion channels, transduce mechanical stimuli (Fig 2).28 Highthreshold nociceptors (VR1 and possibly mDEG/BNaC) may be changed from high- to lowthreshold nociceptors by prior activation (ie, autosensitization) and by sensitizing stimuli.17
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Sodium ion channelsSensory nerves also express sodium ion channels that are especially important in encoding noxious and non-noxious stimuli. Two types of sodium channels have been identified on the basis of their sensitivity to the puffer fish toxin tetrodotoxin (TTX).29 Large-diameter A sensory nerve fibers express only TTX-sensitive (TTXs) sodium channels, whereas smaller A and C fibers express TTXs and TTX-resistant (TTXr) sodium channels.29,30 At least 2 types of sensory-nerve specific (SNS) TTXr sodium channels, SNS/PN3 and SNS2/NaN, contribute to the excitability of nociceptors and the generation of ectopic inputs.30 Neuronal membranes also express a range of voltage-gated calcium channels (VGCC) that may be attenuated by cannabinoid receptor agonists and the anticonvulsant gabapentin, which helps to reduce thermal hyperalgesia and mechanical and cold allodynia.31,32 Spinal cord anatomy and modulationThe spinal cord is the first relay point for somatic sensory information that is relayed to the brain. All afferent sensory nerve fibers enter the spinal cord via the dorsal roots of the spinal nerves and then separate to innervate second-order neurons in the different zones or laminae of the gray matter of the dorsal horn of the spinal cord (Fig 2).33 The dorsal horn laminae comprise layers of functionally distinct cells that form columns extending the length of the spinal cord. The columns contain a large number of second-order excitatory and inhibitory interneurons that receive multiple inputs from surrounding columns and send outputs to the brain and to the ventral (motor) horn.34 The ventral horn contains interneurons and motor neurons that control the muscles of the trunk and limbs, whereas the transition zone between the dorsal and ventral horn (in thoracic and sacral cord segments) contains autonomic preganglionic neurons that mediate involuntary (visceral) functions and transmit some sensory afferent information via multiple parallel circuits to the brain. The large A sensory nerve fibers terminate on neurons predominantly located in laminae III, IV, and V, which project sensory information to the brain and integrate sensory input with descending information from the brain.24 The A afferent nerve fibers terminate in laminae I, the marginal zone, and divide to send branches to laminae V. Laminae I is the most superficial region of the dorsal horn and relays pain and temperature information to the brain.26 Nonmyelinated C fibers terminate in lamina II (the substantia gelatinosa) and send a few branches to laminae I and V. Laminae I and V contain a large number of multireceptive neurons that receive and process information from highand low-threshold peripheral mechanoreceptors.24 Spinal cord neurotransmittersThe A- and Cfiber input to the dorsal horn releases glutamate that preferentially binds to -amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA), kainite, and Nmethyl-D-aspartate (NMDA) ligand-gated sodium and calcium channels. Under normal conditions, NMDA ion channels are blocked by magnesium ion (Mg2+).24 Activation of AMPA receptor ion channels depolarizes
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the membrane, producing fast excitatory postsynaptic potentials that are focused by local and descending inhibitory neurons, many of which corelease the inhibitory substances glycine and -aminobutyric acid (GABA).24,35,36 Fast excitatory potentials carried predominantly by A sensory nerve fibers signal the onset, duration, and location of the noxious stimulus and are responsible for the well localized and relatively transient sharp, pricking, stinging, and stabbing pain that serves to warn and protect the animal from additional tissue damage. Intense thermal or mechanical stimulation increases the quantity of glutamate and substance P released from afferent sensory nerve terminals, activating postsynaptic neurokinin-1 and metabotropic glutamate receptors (mGluR), facilitating and prolonging the release of intracellular calcium and generating plateau potentials by activation of VGCC and nonspecific cation channels.37 The magnitude of these events is proportional to stimulus intensity and is responsible for the removal of the magnesium blocking of NMDA receptors and the generation of a greater and longer (> 10 seconds) postsynaptic depolarizing response, such that pain remains long after the stimulus is removed.38,39 Projection and perceptionSomatic sensory information is projected to the reticular formation of the brain stem and surrounding nuclei by multiple parallel circuits (eg, spinothalamic, spinoreticular, spinomesencephalic, and postsynaptic dorsal column tracts) before converging in the thalamus.40 The relative importance of these nerve tracts in transmitting noxious sensory information to the brain varies considerably among species. Excitatory activity is modulated by a variety of pre- and postsynaptic opioid (,, ) noradrenergic (-1, -2) and muscarinic receptors.41-43 The rostroventromedial medulla is a region that is critical to the integration and processing of ascending nociceptive information and modulation of descending output from the brain.40 This region contains excitatory and inhibitory cells that either facilitate or inhibit nociceptive reflexes and nociresponsive behaviors.44 The thalamus integrates and relays information to the somatosensory cortex, which in turn projects to adjacent cortical association areas, including but not limited to the limbic system.45 The limbic system includes the cingulate gyrus (involved with behavior and emotion), amygdala (conditioned fear and anxiety), hippocampus (memory), hypothalamus (sympathetic autonomic activity), locus coeruleus (arousal, vigilance, behavior), and portions of the periaqueductal gray matter (fight or flight response, stressinduced analgesia).46-48 Neurons projecting from the periaqueductal gray matter control many of the antinociceptive and autonomic responses that follow noxious stimulation.48 Peripheral Sensitization Tissue injury and inflammation lead to a state of pain hypersensitivity during which there is an exaggerated response to noxious stimuli (hyperalgesia) and a reduction in the intensity of the stimulus necessary to initiate pain, such that stimuli that would normally
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Figure 3Schematic diagram of the structures and processes involved in peripheral sensitization. Inflammation and tissue damage induce production of a variety of sensitizing substances, including prostaglandins, histamine, serotonin, bradykinin, cytokines, proteases, norepinephrine, and nerve growth factor. These substances increase intracellular calcium concentration and activate a variety of intracellular signaling cascades, which change high-threshold nociceptors to low-threshold nociceptors and activate silent nocicepetors, resulting in primary hyperalgesia and allodynia. R = Receptor. PKC = Protein kinase C. PKA = Protein kinase A. H+ = Hydrogen ion. K+ = Potassium ion. Na+ = Sodium ion. Ca2+ = Calcium ion. TNF = Tumor necrosis factor . See Figure 1 for remainder of key.

never cause pain begin to do so (ie, allodynia).49 This peripheral sensitization is caused by the release of the contents of damaged tissues at the site of injury into the extracellular environment and the accumulation and release of sensitizing substances from inflammatory cells, including neutrophils, mast cells, macrophages, and lymphocytes. Peripheral sensitization may be augmented by increases in postganglionic sympathetic efferent nerve activity.50 Damaged and inflamed tissues release H+, K+, and ATP and induce enzymes, including proteases (eg, thrombin, trypsin), cyclooxygenase-2 (COX-2), and nitric oxide synthase (NOS).51-53 Inflammatory cells release a wide variety of diverse chemical mediators, including but not limited to serotonin, histamine, bradykinin, prostaglandins (eg, PGE2), cytokines (eg, interleukin [IL]-1, IL-6, and tumor necrosis factor [TNF]-), and growth factors (eg, NGF and leukemia inhibitory factor).51,52 Prostaglandins are formed in response to activation of the arachidonic acid pathway and the up-regulation of COX-2 by cytokines, growth factors, and other inflammatory cells.53,54 Prostaglandin E2 sensitizes primary afferent neurons to bradykinin and other mediators and lowers the activa1350 Vet Med Today: Reference Point

tion threshold of TTXr sodium channels by activating protein kinase (PK) A.55-57 These neuroactive and inflammatory substances constitute a sensitizing soup or cocktail that may activate sensory nerve endings but, more importantly, may work synergistically to sensitize (ie, lower the threshold of) high-threshold nociceptors to mechanical, thermal, or chemical stimuli (Fig 3). Tissue damage and inflammation also contribute to the activation of so-called silent or sleeping nociceptors.58 Activation of silent nociceptors in inflamed joints results in mechanical hypersensitivity and a painful response to normal joint movement.58,59 Inflammation (ie, release of IL-1 and TNF-) and nerve injury also increase the production of NGF which exerts a global influence by reg, ulating the expression of neuropeptides, receptors, and ion channels.51,60-62 Proteases, substance P and CGRP act , on inflammatory, smooth muscle, and endothelial cells, inducing vasodilation and extravasation of fluid and proteins from capillaries, which further amplifies the inflammatory response and contributes to a limited spreading of hypersensitivity to A and C sensory nerve fiber nociceptors immediately adjacent to the area of primary tissue damage.51,57
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Figure 4Schematic diagram of the structures and processes involved in activity-dependent plasticity. Intense or sustained stimuli result in temporal summation and cumulative depolarization of dorsal horn neurons, inducing windup and central sensitization. Release of glutamate and neuropeptides from central C-fiber axons activates ion channels and membrane receptors, leading to increases in intracellular calcium concentration and activation of intracellular signaling cascades in dorsal horn neurons, which amplify responses and trigger gene expression. Central sensitization represents an activity-dependent functional plasticity. BDNF = Brain-derived neurotrophic factor. Sub P = Substance P IP3 = Inositol triphosphate. COX2 = Cyclooxygenase-2. EP = Prostanoid receptor. See Figures . 1 and 2 for remainder of key.

Central Sensitization Mechanical hypersensitivity and secondary hyperalgesia are features of intense or sustained tissue and nerve injury that cannot be explained by changes in the transduction sensitivity of high-threshold peripheral nociceptors, because no change in nociceptor transduction sensitivity can be found outside the area of primary hyperalgesia (ie, in the zone of secondary hyperalgesia). The increase in dorsal horn excitability exaggerates inputs from nociceptors and elicits responses from A fibers that normally would not respond (ie, allodynia).63 Activity-dependent bombardment of nociceptive-specific and nonspecific (wide dynamic range) neurons in the dorsal horn of the spinal cord by afferent C-fibers results in temporal summation and cumulative depolarization (known as windup) of synaptic inputs in dorsal horn neurons.38 Windup is a manifestation of the removal of the magnesium blocking of NMDA receptors, making them more available for activation by glutamate.38,64 Glutamate, substance P, and brain-derived neurotrophic factor (BDNF) play important roles in the induction of central sensitization by activating membrane-bound receptors (eg, NMDA, mGluR, NK, and
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TrkB), which increases intracellular calcium and activates intracellular molecular signaling cascades, including PKC, PKA, NOS, and calcium-calmodulindependent kinase [CaMK]), which further facilitates receptor function and cell surface expression of receptors.63 Activation of the isoform of PKC induces posttranslational changes, including phyophorlyation of membrane receptors and ion channels, which increases neuronal excitability for tens of minutes after cessation of the initiating stimulus, recruits responses to subthreshold stimuli, and is responsible for mediating the transition from short- to long-term hyperexcitability of spinal cord nociresponsive neurons.65 Activation of spinal cord glial cells (ie, microglia and astrocytes) by viruses and bacteria, A- and C-fiber neurotransmitters (eg, substance P and BDNF), and increases in local concentrations of NO and prostaglandins cause hyperexcitability and exaggerated release of substance P and excitatory amino acids from presynaptic pain-transmission neurons.66 The increased excitability in conjunction with decreased inhibition in spinal cord neurons constitutes central sensitization (Fig 4).35,67 Central sensitization increases the response area (ie, receptive field), causes hypersensiVet Med Today: Reference Point 1351

tivity and allodynia, and changes the tissues response characteristics to thermal, mechanical, and chemical stimuli.49 The difference between peripheral and central sensitization is that the former enables low-intensity stimuli to induce pain by activating sensitized A- and Cfiber nociceptors, whereas the latter allows low-threshold A sensory fibers to induce pain by increasing spinal neuron excitability and altering spinal cord sensory processing.68 Central sensitization is presently accepted as a major contributor to post-injury pain hypersensitivity and provides an explanation for the mechanism by which low-threshold A-mechanoreceptors, which normally only elicit innocuous sensations (eg, touch, vibration, and pressure of movement), generate pain. Disinhibition When nerve impulses generated from peripheral sensory nerve fibers reach the dorsal horn of the spinal cord, they are modulated by excitatory and inhibitory influences. Melzack and Wall69 first suggested that inhibitory interneurons in the dorsal horn act as a gate to the central flow of noxious sensory information. Subsequent investigations have revealed that inputs to the dorsal horn that originate from myelinated and unmyelinated peripheral nerves and the brain activate inhibitory interneurons, inducing both tonic and phasic inhibitory effects upon nerve impulses and their projection to the brain.35,70 Tonic or long-lasting and phasic inhibitory activity are mediated by GABA and glycine acting on GABAA and GABAB receptors.71 Blocking both receptors induces pain behaviors (eg, hyperalgesia, allodynia) identical to central sensitization, suggesting that inhibition or removal of descending inhibitory activity (disinhibition) may change the responsiveness of dorsal horn neurons to low-threshold inputs.71 Peripheral nerve injury in particular is associated with increased expression of the endogenous opioid antagonist cholecystokinin (CCK) and a corresponding increase in the CCKB receptor.72 Both responses may act to inhibit the protection induced by release of endogenous opioids and may contribute to the decreased potency of opioids in neuropathic pain. The contribution of disinhibition to acute and chronic pain states has not been fully characterized but is known to be important in pain caused by peripheral nerve injury in which a reduction of A-fiber mediated inhibition of C-fiber activity has been detected.73 Modification Increases or decreases in the signal molecules produced in sensory neurons by inflammation or nerve injury or by spinal cord glial cells are responsible for changes in neuronal phenotype.66,74 The phenotypic switch is triggered by increases in NGF or glial cellderived neurotrophic factor and the production of glial cell-derived proinflammatory cytokines that alter the chemical expression of low-threshold A fibers.66,75,76 Increases in NGF are critical for sensitizing nerves and for triggering intracellular signaling molecules that modulate and modify nerve function by inducing transcription.76 Blocking the peripheral actions of NGF inhibits much of the hyperalgesia induced by inflammation.76 Activity-dependent
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increases in the intracellular concentration of calcium, PKA, and PKC activate a family of mitogen-activated PK (MAPK), which include extracellular signal-regulated kinases, stress-activated PK (c-Jun N-terminal kinase), and p38.77 The MAPK modulate and modify membrane receptor function, effectively increasing spinal neuron excitability and further promoting the development of central sensitization.38 The activation of PKC, PKA, CaMK, and MAPK phosphorylate the transcription factor cAMP response element binding protein (CREB), which has been implicated in transcriptional regulation and expression of pain-related genes in dorsal root ganglia and dorsal horn neurons.77 Activation of CREB is known to contribute to longterm pain hypersensitivity after injury.78 Peripheral nerve injury, like inflammation, induces phenotypic shifts that result in increased expression of substance P and BDNF in the central terminals of A fibers, but unlike inflammation, peripheral nerve injury induces decreases in substance P, CGRP, VR1, and SNS/PN3 in peripheral nerves.79,80 Nerve injury may lead to increases in brain III sodium channel, which mediates ectopic activity in injured nerves, and a decrease in opioid receptors contributing to poor efficacy of opioids in treatment of neuropathic pain.81 Nerve injury may also result in delayed loss of sensory neurons (particularly C fibers) in the dorsal horn of the spinal cord and sprouting of low-threshold myelinated A afferent terminals into portions of the dorsal horn that were once occupied by C fibers.82 Collectively, these changes, in conjunction with a loss of centrally mediated inhibitory mechanisms in the dorsal horn, promote changes in the functional profile of sensory neurons and the development of chronic intractable pain syndromes. Implications for the Development of New Analgesic Therapies Important advances, including but not limited to the discovery of novel peripheral and CNS receptors, the identification of intracellular signal transduction cascades, and the clarification of mechanisms responsible for the transmission and processing of painful sensations, continue to fuel the development and clinical application of new pain therapies (Table 1). The review presented here was intended to provide a rationale for administration of many presently used and novel analgesic therapies, including nonsteroidal antiinflammatory drugs (for inflammation), opioids, -2 agonists (for modulation of excitatory and inhibitory neuronal activity), and local anesthetics (for suppression of electrical impulses). For example, the discovery of TTXr sodium channels (eg, SNS/PN3 and SNS2/NaN) and their preferential expression in C fibers suggests that drugs specifically designed to block these channels may reduce painful sensations without interfering with normal tactile sensations. Furthermore, the identification of specific pain-mediating or potentiating receptors, channels, growth factors, enzymes, transcription factors, and genes has major implications for development of products that may modify their actions and thereby induce analgesic effects. Knowledge of the mechanisms responsible for
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Table 1Treatment of various types of pain by use of drugs that target chemical mediators of pain
Mechanism of pain Peripheral sensitization Type of pain Pressure (static) hyperalgesia Thermal hyperalgesia Spontaneous pain Target Prostaglandin-R; COX-2 V1-R-desensitization B2-R and serotonin-R NK1-R TTXr channels NGF EP-R CB1-R VGCC COX-2 NMDA-R NK1-R Neuronal NOS Protein kinase C TTXs channels TTXr channels Drug NSAID Capsaicin B2 and serotonin antagonists* NK-1 antagonists* TTXr blockers NGF antagonists EP-R (PGE2) blockers CB1 agonists N-type calcium channel blockers COX-2 inhibitors (celecoxib, rofecoxib) NMDA-R antagonists (ketamine, dextram ethorphan) NK-1 antagonists* Neuronal NOS inhibitors Protein kinase C inhibitors TTXs blockers (lidocaine, mepivacaine, ropivacaine, mexilitine) TTXr blockers, Antiepileptic agents (gabapentin, carbamazipine, lamotrigine), Tricyclic antidepressants (amitriptyline) Phentolamine, guanethidine NGF antagonists Opiates (morphine, oxymorphone, methadone, tramadol) -2 agonists (clonidine, medetomidine, dexmedetomidine) Gabapentin Tricyclic antidepressant (amitriptyline) CCK-R antagonists

Central sensitization

Tactile (dynamic) hyperalgesia Cold hyperalgesia Pin-prick hyperalgesia

Ectopic discharge

Spontaneous pain, paraesthesia, neuroma

Sympathetically maintained pain Disinhibition

Spontaneous pain Spontaneous pain Hyperalgesia

-R NGF/trKA Opioid, -2, GABA, NK-1 adenosine, P2X, kainate, mGluR, nACh receptors

CCK-R

*In clinical development. In preclinical development. R = Receptors. COX2 = Cyclooxygenase-2. NSAID = Nonsteroidal anti-inflammatory drug (carprofen, etodolac, ketoprofen, meloxicam). V1 = Vanilloid. B2 = Bradykinin. NK1 = Neurokinin. TTXr = Tetrodotoxin resistant. NGF = Nerve growth factor. EP = Prostanoid. CB1 = Cannabanoid. VGCC = Voltage-gated calcium channels. NMDA-R = N-methyl-D-aspartate receptor. NOS = Nitric oxide synthase. TTXs = Tetrodotoxin sensitive. TrKA = Tyrosine kinase A. GABA = Gamma amino butyric acid. P2X3 = Purine (chemical). mGluR = Metabotropic glutamate receptor. NACh = n-Acetylcholine. CCK = Cholecystokinin.

peripheral sensitization enhances development and administration of drugs or drug combinations that reduce nociceptor activation (eg, local anesthetics and anticonvulsants) and therapies that suppress the inflammatory response (eg, nonsteroidal anti-inflammatory drugs [NSAID] and cryotherapy). The identification of opioid, -2, and prostaglandin receptors in the spinal cord and inflamed tissues argues in favor of the administration of epidural, intra-articular, and intralesional opioids (eg, morphine), -2 agonists (eg, medetomidine), NSAID (eg, ketorolac), and corticosteroids (eg, triamcinolone) for treatment of pain.83 Prevention of central sensitization dictates the administration of analgesic drugs before or soon after pain is established.17 Preemptive pain therapy has the potential to reduce the total amount of analgesic drug required to treat pain in addition to decreasing anesthetic requirements in surgical patients. The consequences of disinhibition may be modified by administering drugs that promote spinal inhibitory mechanisms (eg, -2 agonists and epidural administration of morphine).83 Single-drug analgesic therapies (eg, antihistamines, NSAID, glucocorticosteroids, or opioids) are rarely 100% effective, because so many sensitizers and central mechanisms are involved in modulating and amplifying pain. This opinion is substantiated by clinical experiences in humans and animals that confirm that inflammatory, neuropathic, and cancer pain
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are best treated by a combination of drugs that act by different mechanisms.84 Different pain states require different therapies, and in some instances pain remains resistant to all therapy. Neurochemical differences in specific types of persistent pain are known to mirror the efficacy of different analgesic drugs.85 Morphine, for example, is relatively effective for treating inflammatory pain but is less efficacious for treating neuropathic pain in humans.86 Conversely, tricyclic antidepressants (eg, imipramine and amitriptyline) and several newer anticonvulsants (eg, gabapentin and carbamazepine) are more effective for treating neuropathic than inflammatory pain in humans.87 Several investigators have suggested that the neurochemical changes induced by bone cancer are uniquely different from those induced by inflammation and nerve damage and that bisphosphonates (eg, alendronate, clodronate, and pamidronate) may provide effective pain therapy.88 Results of these studies further suggest that methods for treating clinical pain (inflammatory and neuropathic pain) can be developed that do not interfere with normal nociceptive pain, thereby eliminating the suffering associated with the former while maintaining the protective effects of the latter. Early or preemptive multimodaland mechanism-based therapy should help to prevent the physiological, phenotypic, and behavioral consequences of uncontrolled pain and the nervous systems memory of pain (Appendix).17,83
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Conclusion The immediate (< 1 second) reflexive and nociceptive responses associated with C-fiber input (activation), rapid (seconds) and progressive changes in excitability (windup), development of peripheral and central sensitivity (hours), and activity-dependent alterations in intracellular signal molecules and gene expression that define a potentiated system (hours later), in conjunction with disinhibition and A-mediated pain, represent a series of neurobiological events that are responsible for activation, modulation, and modification of the nervous system by sensory stimuli.39 The myriad of chemical mediators and biochemical cascades responsible for these events provides fertile ground for the development of new analgesic mechanism-based therapies. To attain this goal, clinically validated mechanism-based diagnostic techniques, pain scoring systems, and global outcome measures are required. The present methods for categorizing pain in animals are guided by the same principles as those used for humans and are based upon cause (eg, trauma, arthritis, or pancreatitis), embryologic origin (ie, superficial, visceral, or deep), anatomy (eg, somatic or visceral), body system (eg, neurologic, musculoskeletal, or gastrointestinal), duration (eg, transient, acute, or chronic), and intensity (eg, mild, moderate, or severe).8,89-90 Although essential in helping to identify the disease processes responsible for pain and important for placing patients into broad nociceptive, inflammatory, or neuropathic pain categories, these schemes do not identify the mechanisms responsible for pain and therefore do not suggest the most beneficial therapy. Future mechanism-based pain diagnosis and classification systems would help to overcome this clinically important problem and suggest therapies that alleviate clinical pain without interfering with the protective role provided by physiologic pain.91 The importance of behavioral-based techniques for evaluating pain in animals should not be underemphasized.14 Future clinical trials evaluating the efficacy of old and new analgesic therapies must use systematic, discriminatory, and objective methods for determining the quality, localization, timing, and intensity of pain and how these variables reflect different pain mechanisms.92 Clinically relevant placebo-controlled pharmacokinetic and pharmacodynamic trials must be conducted in veterinary patients with clinical pain, using statistically validated outcome measures.92 Finally, data regarding the prevalence and incidence of the various types of pain that occur in animals with naturally occurring diseases should be gathered and analyzed in order to guide future clinical and experimental trials of therapy for pain. References
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Appendix
Optimizing pain therapy

Evaluate and treat the underlying disease. Evaluate the extent of tissue injury if present. Evaluate the severity of pain (use a pain scoring system), taking into con
sideration animal activity, behavior, environment, and human-animal bond (owner expectations). Severity of pain may have to be assumed in some situations. Individualize dose, route of administration, and frequency of drug administration. Use preemptive, multimodal, synergistic, and adjunctive approaches to pain therapy, including nondrug interventions (cryotherapy, acupuncture, electrostimulation, electromagnetic, nutritional). Evaluate and treat background, breakthrough, and procedural pain. Evaluate and document pain and treatment efficacy at regular intervals. Monitor and record adverse effects or toxicity of treatments.

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