Pain: Neuroanatomy, Chemical Mediators, and Clinical Implications

AACN Clin Issues 2000 May;11(2):168-78McHugh, Jeannette M. RN, PhD*; McHugh, William B. MD, PhD†Section Editor(s): Cheek, Dennis J. RN, PhD; Buxton, Iain L. O. PharmDFrom the *Duke University School of Nursing, Durham, North Carolina, and the †University of Nevada School of Medicine (adjunct clinicalfaculty), Reno, Nevada.Reprint requests to William B. McHugh, MD, PhD, 75 Pringle Way, Suite 910, Reno, NV 89502.

Abstract

Most pain information begins at simple, naked nerve endings called nociceptors that form a functional pain unitwith nearby tissue capillaries and mast cells. Tissue injury causes these nerve terminals to depolarize, an eventthat is propagated along the entire afferent fiber eventuating in sensory impulses reaching the spinal cord. Thisfiring of primary afferent fibers at the site of tissue injury causes axonal release of vesicles containingneuropeptides such as substance P, which acts in an autocrine and paracrine manner to sensitize the nociceptorand increase its rate of firing. Cellular damage and inflammation increase concentrations of other chemicalmediators such as histamine, bradykinin, and prostaglandins in the area surrounding functional pain units. Theseadditional mediators act synergistically to augment the transmission of nociceptive impulses along sensoryafferent fibers. Primary fibers travel from the periphery to the dorsal horn where they synapse on secondaryneurons and interneurons. When activated, interneurons exert inhibitory influences on further pain signaltrafficking. Efferent supraspinal influences, in turn, determine the activity of interneurons by releasing a varietyof neurotransmitter substances, thus resulting in a high degree of modulation of nociception within the dorsalhorn. Events occurring in the periphery and in the dorsal horn can cause a dissociation of pain perception fromthe presence or degree of actual tissue injury. These phenomena involve many chemical mediators and receptorsystems, and can increase pain experience qualitatively, quantitatively, temporally, and spatially. The complexityand plasticity of the nociceptive system can make clinical management of pain difficult. Understanding thestructure and chemical signals associated with this system can improve the use of existing analgesics and providetargets for development of newer and more specific pain-fighting drugs.------------------------------------------------------------------------Organization of Pain Sensation

The system of nerve fibers that carries raw data about temperature, position, and pressure from the peripheraltissues to the central nervous system has an organizational scheme that is similar to that shared by other sensorymodalities. Unlike these other senses, however, the pain system does not have a unique and dedicated receptorcell type. Receptors for light, sound, smell, and taste, responding in a graded linear fashion to the physicalenergy of an applied stimulus, develop a variable electrical generator potential. This generator potential thenactivates its associated nerve fiber, generating impulses that are approximately equivalent in nerve firingfrequency to the intensity of the applied stimulus. Thus, for most of the sense modalities, the intensity of thestimulus energy applied to the receptor is faithfully transmitted to the central nervous system by proportionalreceptor generator potential and frequency of nerve impulse formation.1

In the common organizational structure of the sensory nervous system, a given receptor is served by a nerve fiberfrom a cell body located in the dorsal root ganglion adjacent to the spinal cord (Fig. 1). Impulses traveling alongfirst-order neurons synapse on second-order neurons in the dorsal horn of the spinal cord, the axon of whichcrosses to the contralateral side and ascends to synapse on third-order neurons. The third-order neurons sendfibers to the cortex where conscious awareness of the sensation occurs.

Figure 1. Organization of pain sensation. Nonspecific nociceptive fibers are found in tissues in proximity tocapillaries and mast cells. All three of these elements respond to tissue injury in a coordinated fashion with theinflammatory process. Cell injury (leakage of proteases, decreases in interstitial pH), membrane disruption(consequent arachidonic acid metabolism), mast cell degranulation, plasma exudation (bradykinin formation)and capillary dilation all impose chemical and mechanical stimulation of the nociceptor. Impulses arrive at thecell body in the dorsal root ganglion and travel along projections to secondary afferent nerves in the dorsal horn.Impulses then cross to spinal thalamic tracts on the opposite side of the cord before ascending to the thalamuswhere pain begins to become a conscious event. Pain impulses are associated with meaning and responses asthey are processed at higher cortical centers.

Unlike other sensory receptors, nociceptors are unspecialized, naked nerve endings adjacent to small bloodvessels and mast cells. This structural triad of capillary, nociceptor, and mast cell represents a functional

nociceptive response unit, which issensitive to tissue damage. Thisnociceptive unit responds topotentially injurious stimuli byinitiating an inflammatoryresponse ( i .e . , mast cel ldegranulation). Inflammationcauses release of chemicalmediators such as histamine intothe involved tissues, whilestimulating the nerve fiber.2Although fairly nonspecialized,nociceptive nerve endingsdemonstrate some variation inresponse to physical stimuli.Although much pain sensationtravels through sensory C fibers,those receptors sensitive toextremes of temperature andpressure transmit impulses over high-threshold polymodal A([DELTA]) fibers. These fibers can often servenociceptive functions.

Tissues are also richly supplied with a population of small nerve fibers that remain inactive in signalingnociception until the unit is sensitized by chemical mediators of inflammation.3 All simple nociceptive fibers areof small diameter and are either unmyelinated (C fibers) or lightly myelinated (A[DELTA]). Thus, nerve tractsassociated with nociception generally conduct slowly, at rates of less than 5 m/second, a conduction velocity thatis less than 10% of that of motor fibers. Although most sensory experiences such as vision and hearing do notbecome conscious events until neural impulses reach appropriate parts of the cortex, pain appears to reachconscious awareness precortically in the thalamus.4 Sensory fibers from high-threshold (temperature andpressure) polymodal receptors synapse with a specialized second-order neuron, the wide dynamic range (WDR)neurons. The WDR neurons also serve as conduits for nonnociceptive impulses from low-threshold mechanicalreceptors and thermal receptors. Thus, although nociceptive-specific neurons receive restricted input and respondonly to noxious stimulation, WDR neurons respond to a range of stimulus intensities from light touch to painfulpressure with increasing firing frequencies.3

Fibers associated with pain, whether nociceptive-specific or high-threshold polymodal afferent fibers, synapsewith interneurons and with second-order neurons. The function of these interneurons is most likely to inhibit ordecrease the frequency of firing of both types of second-order neurons (Fig. 2). Additional input, both inhibitoryand facilitatory, arises from supraspinal centers and travels down spinal tracts to modulate events in the dorsalhorn. This supraspinal influence is exerted presynaptically, on the incoming nociceptive fibers, andpostsynaptically on the secondary nociceptive and WDR neuron cell bodies.4

Figure 2. Central integration ofnociception. Activity in the dorsalhorn (indicated by shaded area)modulates and integrates paintransmission. Tissue injury canstimulate both nociceptors ornonspec ia l i zed (po lymoda l )receptors. Post-dorsal root ganglionfibers enter the spinal cord andsynapse in the dorsal horn withsecondary nerve cell bodies andinterneurons (I). Interneuronsgenerally exert an inhibitoryinfluence on activity of secondaryneurons. Interneurons, however,receive either facilitatory orinhibitory input from supraspinalcenters (periaqueductal gray matter

and ventral medulla). The net effect of these events strongly influences the intensity of firing of secondaryneurons and the cumulative pain information sent to higher centers.

Relationship between Nociception and Pain

Nociception arises from receptor units that detect tissue damage. However, nociception is not synonymous withpain, a phenomenon understood as "an unpleasant sensory and emotional experience associated with actual orpotential tissue damage, or ... described in terms of such damage."5 Indeed, pain remains a clinical conundrum inwhich it is often disassociated from actual injury. Pain can be experienced in excess of any tissue injury or evenin the absence of tissue damage. Alternatively, pain is sometimes absent when tissue damage is obvious andongoing.1 In several ways, the disconnect between the pain perception system and parallel tissue injury is acommon human experience. An inflamed body part, for example, "looks painful" and is often associated withhyperalgesia, being more sensitive to painful stimuli than nearby noninflamed tissues. Similarly, inflamed tissuescan be more sensitive to nonnoxious stimuli (hyperesthesia), and these nonnoxious stimuli are often"misperceived" as pain (allodynia). In addition, hyperalgesia in an inflamed body part may be spread spatiallyand be felt in remote noninflamed areas. This remote hypersensitivity is known as secondary hyperalgesia.1

Finally, the phenomenon of chronic pain is perhaps the most troubling example of the dissociation of pain andtissue injury. Because chronic pain is often refractory to treatment, it is distressing to patients and frustrating forclinicians. In a chronic context, conscious pain experience and associated behavioral responses continue despitesatisfactory tissue healing and absence of any obvious cause for continued nociception.6 The experiential andbehavioral elements of acute and chronic pain involve the not easily quantifiable quality of suffering. Thisexperience can be understood as the negative responses induced by pain involving fear, anxiety, stress, and senseof loss. Suffering can only be inferred from animal models, and because it is best assessed in human subjects, itremains an elusive problem in the intensely plowed field of pain research.7

Tissue Injury and Nociceptor Activity

Injury to tissues by physical (mechanical, thermal), chemical (toxins, tissue proteases), or immunologic meansresults in local accumulation of chemical mediators that can strongly activate nociceptive units 1 (Fig. 3). Cellmembrane perturbation by injurious agents or forces causes activation of membrane-bound enzymes(particularly phospholipase A2) which releases arachidonate from membrane phospholipids 8 (see Table 1 for anexpanded list of pain mediators). Arachidonic acid is the beginning substrate for enzymatic cascades thatgenerate prostaglandins, thromboxanes, and leukotrienes. In addition, tissue injury initiates enzymatic cleavageof circulating high-molecular-weight kininogen to produce bradykinin, a potent mediator of pain andinflammation.1 Further, mast cells in damaged tissues degranulate releasing histamine and chemotactic agentsthat promote infiltration of injured tissues with neutrophils and eosinophils.8

Figure 3. Cell injury causesactivation and sensitization ofnociceptor. (1) Injurious stimulus; (2)products of arachidonate released byperturbed cells and degranulatingmast cells; (3) histamine and otherinflammatory substances releasedfrom mast cell vesicles; (4) injuryand mediators causing nociceptors toproduce generator potential anddepolarize fiber; (5) axonal "reflex"releasing vesicles on axonalextremities of primary afferent fiber;(6) consequence of action of severalchemical mediators' elevation of fiber resting membrane potential (RMP). Fiber closer to threshold (Th) morelikely to fire.

TABLE 1 Pain Mediators

Many tissue injury-induced chemicalmediators (such as histamine, bradykinin,and prostaglandins) cause dilation andincreased permeability of tissue capillaries.In addition to causing localized edema, theextravasation of plasma slows transit ofcellular constituents of blood and favorsmargination of leukocytes to capillaries ofthe injured tissue bed.8 Activated plateletaggregation in these capillaries isassociated with the release of serotonin,another mediator of pain andinflammation. Leukotriene B4 from mastcell granules and injured cells is also apowerful chemoattractant for neutrophilsand monocytes and is a stimulant ofsuperoxide generation. Accumulation andactivation of inflammatory cells iscytotoxic to invading organisms but is also indiscriminately damaging to nearby host cells.8

The accumulation of edema fluid in a tissue bed produces mechanical pressure that activates nonspecific sensoryneurons. In addition, prostaglandins lower the firing threshold of nociceptors, sensitizing them to any chemicalor mechanical stimulus.1 Bradykinin is an extremely potent activator of primary sensory neurons. Sensory Cfibers, which can be caused to fire by bradykinin, are richly supplied with neuropeptide-containing vesicles intheir distal axons. These neuropeptides (sometimes referred to as tachykinins) include substance P (SP),neurokinin A, and calcitonin gene-related peptide. Depolarization of sensory C fibers results in the axonalrelease of neuropeptides which, in turn, further promote inflammation by increasing capillary dilation andpermeability, as well as leukocyte chemotaxis and activation.8

Self-Propagation of Nociception by Sensory Nerve Fibers

In addition to tachykinins, stimulated nociceptive nerve fibers both release and respond to glutamate. They alsohave been found to release peptides such as cholecystokinin (CCK), somatostatin, and galanin, although theactions of these neurotransmitter substances remains unclear.9 It is known that nociceptive fibers have receptorsfor glutamate and SP, and that activation of these receptors stimulates the nerve fiber resulting in nociceptiveinformation being sent to the neurons in the dorsal horn.10 Cell injury and inflammation cause a decline in tissuepH and the release or production of purines. Ion channels in sensory nerve fibers are influenced by these pHchanges to elevate nerve fiber resting membrane potential, placing it closer to threshold.11 Activation ofpurinergic receptors appears in turn to cause increased neuronal glutamate release.12 In summary, products ofcell injury and inflammatory mediators initiate multiple overlapping and redundant processes that cause therelease of glutamate and SP (and probably other neurotransmitters), which, acting in autocrine and paracrinefashion, further activate neuron receptors resulting in increased impulse generation in the nociceptive fiber.

In addition to intensifying the impulse formation of active sensory fibers, inflammation also converts previouslyquiescent nociceptive fibers into fibers capable of responding to real or potential tissue damage. In part, thisconversion takes place by increasing the number of receptors for glutamate on the fiber.13 Prostaglandins appearto initiate this process, as do bradykinin and histamine. In addition, nerve growth factor production by neuron-insulating Schwann cells and tissue fibroblasts is increased in states of inflammation. Nerve growth factor hasalso been implicated in the sensitization process, particularly for those fibers that produce SP and similarpeptides.14

Nonlinear Dynamics of Nociception: Mechanisms and Mediators

Despite the importance of inflammation in nociception, pain is often perceived almost simultaneously withinjury, well before the development of the inflammatory process. Initial pain sensation is transmitted alongA[DELTA] fibers and is sharp and discrete. Subsequent pain sensations are transmitted by C fibers and becomediffuse and burning in quality. Both A[DELTA] and C fibers use SP and glutamate as cotransmitters (althoughpolymodal C-fiber transmission appears more dependent on SP).15 Experiments with a variety of SP inhibitors,

however, have raised questions about the relative importance of glutamate and SP in this process. Inhibition ofSP receptors causes change in initial pain perception but without abolishing it, suggesting that this event is SPindependent.16 Similarly, knockout mice that do not have the gene for the SP precursor or the SP receptorremain capable of experiencing pain, although their responses to severe pain are attenuated. These data suggestthat glutamate, rather than SP, is the transmitter for initial pain sensation and that the role of SP is more complexthan previously thought.17

The nociceptive system, unlike other sensory systems has a variable input-output ratio. Simply put, this meansthat a given noxious stimulus may produce little or much pain, depending on the state of the system and theorganism as a whole. Increasing receptor sensitivity can bias the system to higher output (that is, more painsignaling per unit of stimulation). Indeed, it is by increasing receptor sensitivity that the previously mentioned C-fiber axon reflex increases pain fiber output for each nociceptor input.1 This mechanism, which is not a reflex inthe classic sense, but rather is an axonal response in an area of stimulation, occurs because axons conductimpulses in both directions. Thus an axon stimulated in one area depolarizes and releases mediators in anadjacent area.1 A visible example of this axonal release is the wheal-and-flare response to local allergensensitivity in the skin. Histamine released from damaged skin cells and mast cells stimulate intradermalnociceptive axons, which release SP and other neuropeptides into adjacent tissue areas. These peptides producevasodilation, increased capillary permeability, leukocyte migration, and release of more histamine, as well asbradykinin and more SP. The importance of neuropeptides in this mechanism is demonstrated by knockout micethat do not have the the gene for SP precursor or for the NK-1 (SP) receptor. These animals do not manifest axonreflex reactions.17 Additionally; they demonstrate a significant attenuation of the expected hyperalgesia andallodynia after tissue injury.18

Opioid receptors are present on some small nociceptive fibers, and activation of these receptors by endogenousopioids (enkephalins) or exogenously administered opiates appears to antagonize the acute effects of SP andglutamate. Further, opiates may reduce axonal SP release and prevent the increase in SP receptors that occurs ininflammatory states (i.e., the activation of quiescent C fibers).19,20 These acute effects of opiates disappearquickly, and this apparent tachyphylaxis may be related to the antagonism by other peptides such as CCK,because attenuation of morphine analgesia can be reversed by CCK receptor antagonists. It is postulated thatCCK release is involved in the modulation of peripheral nociception.21

Central Integration of Nociception

Although some modification of nociceptive sensitivity takes place in the tissues, the site for primary integrationof segmental pain information is the dorsal horn of the spinal cord (and its craniocervical analog, the spinal tractof the trigeminal nerve). It is here that raw information from tissue beds throughout the body is modulated byand integrated with supraspinal and other nervous system input. Cells specialized to transmit pain information liein the uppermost lamina of the dorsal horn and receive input only from nociceptive fibers. This information maybe modality-specific input (e.g., extremes of temperature or pressure) or may result from impulses generated bynonspecific tissue damage (for example low pH or noxious chemicals). The WDR neurons are located deeper inthe dorsal horn and receive input from nociceptive fibers as well as from fibers serving receptors for pressure,temperature, and touch.4

The neurotransmitters from these nonnociceptive fibers are excitatory amino acids, particularly glutamate.Although nociceptor-associated fiber transmission largely involves neuropeptide (SP) release, glutamate hasoverlapping participation in exciting these pathways.18

Axons from nociceptive neurons as well as from neurons conveying other sensory information make synapticcontact in the spinal cord with interneurons.1 These interneurons also synapse with and influence both types ofsecondary neurons, the nociceptive-specific and WDR neurons. In general, interneurons are inhibitory. Theyexert this influence by releasing [gamma]-aminobutyric acid (GABA), glycine, and possibly a peptide opioidinto synapses they share with first- and second-order neurons.1 Inhibition of sensory input may occur by twomechanisms. First, release of neurotransmitters from interneurons may cause primary afferent hyperpolarization.This form of presynaptic inhibition is usually mediated by GABA expressed on incoming afferent fibers.8 Thishyperpolarization then results in reduced release of excitatory neurotransmitters (glutamate and SP) and lessimpulse propagation to second-order neurons. Secondly, interneurons may exert postsynaptic inhibition at asecond-order neuron cell body, thus affecting a wide range of neuronal activities.1 The mediators involved inpostsynaptic inhibition may include peptide opioids and the amino acid glycine.8 Norepinephrine, serotonin, oracetylcholine from neurons of supraspinal origin may also exert postsynaptic inhibition.3

Central Integration and the Phenomenon of Windup

As mentioned, there can be a marked dissociation of qualitative pain experience and the nature and severity ofinitiating events in the tissues from which the original impulses arise.1 A major contributor to this importantcharacteristic of the nociceptive system is a central integration of neural input that occurs in the spinal cord. Thisprocess, called windup, is due to a variable relationship between afferent fiber input and spinal cord output to thebrain, which eventuates in pain perception.22 The WDR neurons are most prominently involved in windupbecause they receive convergent input from nociceptive (particularly sensory C) fibers, and nonnociceptivefibers.23 Under conditions of intense input (stimulus rates of more than 0.33 cycles per second) the second-orderneuron fires more rapidly because of persistent partial depolarization.22 Two mechanisms that can cause WDRneuron windup are increased afferent input from inflammation-induced sensitization of first-order fibers, and/ordecreased inhibitory modulation by interneurons.2

Windup and other forms of central (spinal cord) sensitization are caused by the corelease of neurokinins andglutamate from the afferents of first-order neurons and can be blocked by SP inhibitors and by glutamateantagonists that act at the N-methyl-D-aspartate (NMDA) receptor. Central sensitization does not occur inanimals with a genetically caused absence of SP precursors or the NK-1 receptor.15, 17 Furthermore, althoughNMDA inhibitors do not abolish pain perception, they cause a change in input-output ratios of second-orderneurons.24 The increased neuronal firing of windup is initiated when glutamate, released by incoming afferentfibers, acts presynaptically to increase SP release. The glutamate molecules also act postsynaptically activatingnitric oxide synthase. The resultant nitric oxide is thought to diffuse readily to presynaptic terminals where it inturn increases the release of glutamate.25 Substance P released by the incoming afferent neuron acts on theNMDA receptor on the membranes of second-order neurons by removing an inhibitory Mg2+ ion that occupiesthe receptor channel. This has the effect of increasing channel sensitivity to glutamate. It has been theorized thatglutamate, which can be toxic to neurons in high concentration, may permanently damage inhibitoryinterneurons, making the high-output (wound-up) state permanent.16 Conversely, windup can be blocked byinhibitors of nitric oxide synthase, and also by anti-inflammatory drugs such as corticosteroids andcyclooxygenase inhibitors. These agents act by reducing inflammation-induced hypersensitivity of the first-orderafferent neuron.3

The mediators and central neurons involved in windup are a target for treatments to ameliorate pain. Inhibitors ofNMDA such as ketamine have been used experimentally in humans to prevent or reverse central painsensitization.26 However, the effects of these agents (which include sedation and hallucinations) severely limittheir clinical application.16 More promising is the observation that adequate use of opiates during states of acutepain can prevent both peripheral and central pain sensitization. Opiates reduce the release of SP from nociceptivefibers 27 and act centrally, exerting both pre- and postsynaptic inhibition, thus reducing windup. Opiate-inducedpresynaptic inhibition probably acts by reducing SP release from incoming nociceptive afferents. Thepostsynaptic inhibition is caused by hyperpolarization of second-order nociceptive neurons in the dorsal horn.Nevertheless, once windup has been established, it is refractory to inhibition by opiates. The NMDA inhibitors,however, appear to remain effective in reversing hypersensitivity.3

Central Integration: Supraspinal Influences on Pain

There are alterations to pain sensitivity that occur at spinal levels but have their origin in higher centers. Theconcept of central inhibition of pain sensation by supraspinal input is well established and dates from clinicalobservations and electrical stimulation studies. Areas in the midbrain, pons, and medulla, particularly areasaround the cerebral aqueduct (periaqueductal gray matter), have been observed to induce analgesia whenelectrically stimulated.1 These areas of the brain have been found to be rich in endogenous opioids and opioidreceptors. They also have been noted to give rise to fiber tracts that project to the dorsal horn where they releaseserotonin, norepinephrine, and acetylcholine. These fibers terminate on and with both incoming nociceptiveafferent fibers and second-order nociceptive neurons in the dorsal horn.1 They act to inhibit nociceptive inputfrom afferents and/or output by nociceptive second-order neurons.

The inhibitory action of serotonin on structures of the dorsal horn may be mediated by activation of opioid-releasing interneurons. Naloxone, an opioid antagonist, attenuates the analgesic effect of intraspinal serotonin;similarly, serotonin antagonists interfere with analgesic effects of morphine infused in or near the spinal cord.3The analgesic effects of norepinephrine and [alpha]2 receptor agonists such as clonidine are not as wellunderstood. They are not blocked by opioid antagonists such as naloxone, although the analgesic effect ofmorphine is blocked by [alpha]2 receptor antagonists. Tricyclic antidepressants (which prolong the action ofnorepinephrine and serotonin) and selective serotonin uptake inhibitors have been observed to provide

amelioration of chronic pain for some patients. This effect may be explained in part by the increased duration orconcentration of serotonin and norepinephrine in synapses associated with central pain integration.3

Supraspinal influences on the spinal cord are not exclusively inhibitory, because central facilitation can causeincreased responsiveness of spinal nociceptive neurons to incoming nerve impulses. This central facilitation bythe brain probably originates in structures that lie in the ventral medulla where stimulation produces pain-likebehavior. Descending fibers from this region appear to enhance pain transmission by releasing SP, CCK, andexcitatory amino acids such as glutamate. The experience of tissue hypersensitivity produced by supraspinalfacilitation can occur in uninjured areas adjacent to or even distant from sites of inflammation. Thus, themechanism of supraspinal facilitation may contribute to the phenomenon of secondary hyperalgesia after injuryand inflammation.16

Activation of the ventral medulla appears to be involved in symptoms associated with acute opiate withdrawal inan animal with acquired opiate tolerance. Sudden decreases in circulation opiates produce a massive release ofexcitatory amino acids and peptides in the spinal cord, leading to a marked, widespread hypersensitivity tomultiple stimuli.28 Supraspinal facilitation, in addition to windup, has been postulated to contribute to chronicpain states that persist after inflammation and injury have healed.16Implications for Practice

Better understanding of the neurophysiology of pain is beginning to influence clinical practice. In particular,prevention of the windup phenomenon and its long-term sequelae has become a central focus in painmanagement. For example, the heretofore established clinical practice of ordering pain medication on an as-needed basis has given way to scheduled regimens. Similarly, earlier use of more potent analgesics has beenfound to reduce development of chronic pain complications. For these purposes, sustained-release opiatepreparations have been found to provide substantial pain control for some patients, while reducing breakthroughpain and associated adverse effects.29 Additionally, the awareness that opiates have both peripheral and centralanalgesic effects has led to reconsideration of their use in conditions such as arthritis in which they hadpreviously been avoided.30 At the same time anti-inflammatory agents that prevent or reduce peripheralsensitization cannot be neglected as an important adjunct in comprehensive pain management.

Norepinephrine and serotonin reuptake blocking agents were recognized to modulate chronic pain long beforetheir mechanism of action was understood. The awareness that increased concentrations of theseneurotransmitters in the central nervous system inhibit pain impulse transmission has led to a search for otheragents with similar actions. The effectiveness of the anticonvulsant gabapentin in the treatment of neuropathicpain is probably due to its ability to facilitate GABA activity and possibly prevent glutamate release.31 Furtherresearch may provide a spectrum of agents with glutamate receptor blocking activity. Drugs with this therapeuticprofile, if free of the hallucinogenic side effects of current agents, may be useful in preventing or reversing statesof central pain sensitivity in a wide variety of chronic pain states.16

Detecting and responding to real or potential tissue damage seems to be a fairly simple and primitive function.Nonetheless, nociception in higher animals and man is accomplished by a complex system of nerves andmediators that is not static or hard wired but is subject to considerable plasticity. Pain sensation and subsequentresponses to it must be integrated with the overall needs of the organism to serve survival purposes. Spinalsensitization may function teleologically to force rest and inactivity and to promote healing. In othercircumstances, suppression of pain responses may temporally preserve the organism's ability to function in theface of acute stress and immediate threat. The complexity and plasticity of the nociceptive system not onlyserves survival needs but also provides potential targets for pharmacologic modulation of human suffering.

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KEYWORDS: pain; neurophysiology; neurotransmittersAccession Number: 00044067-200005000-00003