analgesia, antinocicepção, dor

7/30/2019 analgesia, antinocicepo, dor

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W. RiedelG. Neeck

Nociception, pain, and antinociception:

current concepts

Z Rheumatol 60:404415 (2001) Steinkopff Verlag 2001

ZfRh

347

MAIN TOPIC

W. Riedel ())

Max-Planck-Institut fr physiologischeund klinische ForschungW.-G.-Kerckhoff-InstitutParkstrae 161231 Bad Nauheim, Germany

G. NeeckStiftung W.G. KerckhoffHerz- und RheumazentrumAbteilung RheumatologieLudwigstrae 373961231 Bad Nauheim, Germany

Nozizeption, Schmerz undAntinozizeption

n

Summary The physiology ofnociception involves a complexinteraction of peripheral and cen-tral nervous system (CNS) struc-tures, extending from the skin, theviscera and the musculoskeletaltissues to the cerebral cortex. Thepathophysiology of chronic painshows alterations of normal phys-iological pathways, giving rise tohyperalgesia or allodynia. Afterintegration in the spinal cord, no-ciceptive information is trans-ferred to thalamic structures be-fore it reaches the somatosensorycortex. Each of these levels of theCNS contain modulatory mecha-nisms. The two most importantsystems in modulating nocicep-tion and antinociception, the N-

methyl-D-aspartate (NMDA) andopioid receptor system, show aclose distribution pattern in nearly

all CNS regions, and activation ofNMDA receptors has been foundto contribute to the hyperalgesiaassociated with nerve injury orinflammation. Apart from sub-stance P (SP), the major facilita-tory effect in nociception is ex-erted by glutamate as the naturalactivator of NMDA receptors.Stimulation of ionotropic NMDAreceptors causes intraneuronalelevation of Ca2+ which stimulatesnitric oxide synthase (NOS) andthe production of nitric oxide(NO). NO as a gaseous moleculediffuses out from the neuron andby action on guanylyl cyclase, NOstimulates in neighboring neuronsthe formation of cGMP. Dependingon the expression of cGMP-con-trolled ion channels in targetneurons, NO may act excitatory orinhibitory. NO has been implicatedin the development of hyperexcit-ability, resulting in hyperalgesia orallodynia, by increasing nocicep-tive transmitters at their centralterminals. Among the three sub-types of opioid receptors, l- and d-receptors either inhibit or po-tentiate NMDA receptor-mediatedevents, while j opioids antagonizeNMDA receptor-mediated activity.Recently, CRH has been found toact at all levels of the neuraxis toproduce analgesia. Modulation of

nociception occurs at all levels ofthe neuraxis, thus, eliciting themultidimensional experience of

pain involving sensory-discrimi-native, affective-motivational,cognitive and locomotor compo-nents.

n Zusammenfassung Die Physio-logie der Schmerzwahrnehmungberuht auf einer komplexen Inter-aktion peripherer, spinaler undsupraspinaler Strukturen des Zen-tralnervensystems (ZNS). Auf je-der Ebene des ZNS erfolgt eineModulation nozizeptiver Informa-tion, wobei die zwei wichtigstenTransmittersysteme der Nozizepti-on und der Antinozizeption, dasN-methyl-D-aspartate (NMDA)-und das Opioid-Receptor System,eine nahezu identische Verteilungzeigen. Glutamat, der natrlicheexzitatorische Transmitter allerNeurone mit ionotropen NMDA-Rezeptoren, bewirkt durch ffnendes Ca2+-Kanals ber die damitverbundene Aktivierung der in-traneuronalen Stickoxidsynthasedie Freisetzung von Stickoxid(NO). Diffusion des NO in Nach-barneurone erhht deren cGMP-Synthese verbunden mit einer er-hhten neuronalen Aktivitt, wel-che sich als Hyperalgesie oder Al-lodynie uert, wenn Transmitteraus nozizeptiven Nervenendigun-gen freigesetzt werden. Die peri-phere Sensibilisierung nozizepti-


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405W. Riedel and G. NeeckNociception, pain, and antinociception: current concepts

ver Axone erfolgt meist ber Se-rotonin, Bradykinin oder Prosta-glandine. Whrend die l- und d-Opioid-Rezeptoren die NMDA-Re-zeptor vermittelte Nozizeptionhemmen oder verstrken, antago-nisieren j-Opioide NMDA-Rezep-

tor vermittelte Reaktionen voll-stndig. Hingegen wirkt Cortico-tropin-relasing-Hormon auf allenEbenen des ZNS antinozizeptiv.

n Key words Nociception glutamate NMDA nitric oxide sensitization opioids spinal cord brainstem cerebral cortex pain periaqueductal grey basal ganglia

descending antinociception

n Schlsselwrter Nozizeption Glutamat NMDA Stickoxid Sensibilisierung Opioide Rckenmark Hirnstamm Kortex Schmerz zentrales Hhlengrau Basalganglien deszendierende

Antinozizeption

Introduction

The integrity of all living organisms is guaranteedby interaction of two highly specialized systems: theimmune system and by the ability of the brain to de-tect and remember danger. Whereas under physio-logical conditions the activities of the immune sys-

tem never reach consciousness, pain immediatelyalerts the organism to the presence of damagingstimuli. Although both the immune and the nocicep-tive system appear to have been evolved separately,it is evident that during evolution mutual communi-cation pathways have been developed by sharingcommon signal molecules and receptor mechanisms(9). Pain is usually defined as an unpleasant sen-sory and emotional experience associated with ac-tual or potential tissue damage. Pain is always sub-

jective, each individual learns the application of theword through experiences related to injury in earlylife (79). Pain is not homogeneous and comprises

three categories: physiological, inflammatory, andneuropathic pain. Pain is entirely a function of cere-brocortical structures composed of discriminative,affective-motivational, cognitive and locomotor com-ponents. Acute pain is mostly short-lasting becausepowerful antinociceptive mechanisms are simulta-neously turned on by the noxious stimulus. Chronicpain is frequently associated with degenerative tissuediseases such as rheumatoid arthritis, does notspontaneously resolve and serves no obvious usefulbiological function (70), and it may be that for thatreason genes favoring an opposing force to chronicpain have not been developed during evolution.

Physiological pain

Physiological pain is initiated with the generation ofaction potentials of specialized sensory nociceptor fi-bers innervating peripheral tissues. The action poten-tials transmitting somatic pain are conducted to theCNS by forming a three-neuron chain transferring no-

ciception to the cerebral cortex. The first-order neu-rons with their cell bodies in the dorsal root ganglionend in the dorsal horn of the spinal cord, the trigem-inal nociceptors in the trigeminal sensory nuclei of thebrainstem, and synapse there with the second-orderneurons, which axons ascend in the spinothalamictract to the thalamus. The third-order neurons projectto the postcentral gyrus of the cerebral cortex, whereinformation is somatotopically organized. Most noci-ceptive signals originating from visceral organs reachthe CNS via afferent fibers in sympathetic nerves. Spe-cific visceral nociceptors have been found in the heart,lungs, testes and biliary system, whereas noxious stim-ulation of the gastro-intestinal tract appears to be de-tected mainly by non-specific visceral receptors thatuse an inensity-encoding mechanism (23, 49). Visceralnociceptive messages are conveyed to the spinal cordby relatively few visceral afferent fibers which activatemany central neurons by extensive functional diver-gence through polysynaptic pathways (18, 59). Im-pulses in visceral afferent fibers excite spinal cord neu-rons also driven by somatic inputs from the corre-sponding dermatome. Noxious intensities of visceralstimulation are needed to activate viscero-somaticneurons, most of which can also be excited by noxiousstimulation of their somatic receptive fields. Thus, vis-ceral pain is the consequence of a diffuse activation ofsomato-sensory nociceptive systems which preventsaccurate spatial discrimination or localization of thestimuli. Although a specific ascending pathway for vis-ceral nociception has not been found, projection ofviscero-somatic neurons include the spino-reticularand spino-thalamic tracts which trigger general reac-tions of alertness and arousal and evoke unpleasant

and poorly localized sensory experiences.

Clinical pain

Inflammatory pain is initiated by unspecific stimula-tion of the sensory innervation of tissues by media-tors released during the interaction of the immune


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system with alien matter. Neuropathic pain, causedby either peripheral or central nervous system le-sions, is the most common form of opioid-poorly-re-sponsive pain. Both forms of pain are characterizedby hypersensitivity at the site of damage and in ad-

jacent normal tissue. Allodynia, either mechanical orthermal, arises from stimuli which never normally

cause pain, while greater and prolonged pain result-ing from noxious stimuli manifests itself as hyperal-gesia.

First-order nociceptive neurons

The sensation of pain that is experienced arrives inthe CNS by mean of two pathways: a sensory discri-minative system which analyzes the nature, location,intensity and duration of nociceptive stimulation, se-parated from a second, phylogenetically newer sys-tem which carries the affective-motivational compo-

nent of pain (33, 83). The peripheral nociceptorsform two classes: myelinated Ad mechanoreceptorand unmyelinated C polymodal fibers (103). As illus-trated in Fig. 1, the majority of these neurons termi-nates in the superficial region of the dorsal horn in-nervating cell bodies of laminae I and II, as distin-guished by their cytoarchitecture (85), while someAd fibers terminate in lamina V (33, 43, 78). The no-ciceptive afferents terminating in the dorsal horn re-lease numerous transmitters, of which some act di-rectly, while some serve as modulators. Under nor-mal conditions, high levels of the excitatory amino

acids glutamate and aspartate, substance P (SP) andcalcitonin gene-related peptide (CGRP) have beenfound in the superficial dorsal horn and are, there-fore, considered as the main nociceptive transmittersunder physiological conditions, while various othertransmitters, colocalized and expressed in both setsof nociceptive afferents, seem to be mainly elevated

under pathological conditions including their recep-tors.

Peripheral sensitization

Nociceptor sensitization underlies the phenomenonof peripheral hyperalgesia that results in an increasein the perception of and response to pain. Severalmechanisms have been proposed to account for hy-peralgesia including direct activation of nociceptorsas well as sensitization of nociceptors through theproduction of prostanoids or the release of various

mediators during tissue injury, inflammation or an-oxia and low pH (37). Especially kallidin and brady-kinin (BK), derived from kininogen precursors fol-lowing activation of tissue and plasma kallikreins bypathophysiological stimuli, appear to be implicatedin the etiology of a number of pain conditions, asso-ciated with inflammation and rheumatoid diseases.Most actions of BK, including the acute activation ofpain, are mediated through the membrane-bound B2receptor, coupled with a G protein. B2 receptors havebeen localized to nociceptive nerve terminals inskin, skeletal muscle, joints and visceral organs (42,48, 55, 60, 75, 76). Via the G protein BK activates in-

traneuronally phospholipase C to generate diacylgly-cerol, which, in turn, activates protein kinase C(PKC), which regulates ion channels and therebyneuronal excitability. Via diacylglycerol, BK stimu-lates the production of arachidonic acid. Prosta-noids, especially prostaglandin E2 and I2, act on no-ciceptors to induce sensitization of the neuronalmembrane (57). The activation of sensory fibers byBK also causes the release of neuropeptides such asSP, neurokinin A (NKA) and CGRP (6). In a recipro-cal fashion, however, prostaglandins can sensitizenociceptors, Ad as well as C fibers, to the action ofBK, as well as several other stimuli, including seroto-

nin (1, 88).

The dorsal horn of the spinal cord

In addition to the transmitters involved in pain sen-sation derived from the primary afferent fibers, thedorsal horn contains various other neuropeptidesoriginating from neurons intrisic to the dorsal horn,

406 Zeitschrift fr Rheumatologie, Band 60, Heft 6 (2001) Steinkopff Verlag 2001

Fig. 1 Distribution of cutaneous and muscle afferent fibers to spinal greymatter


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or from descending axon terminals of neurons withcell bodies located in the brainstem (11, 12). Thelaminae I, II, V, VI and X of the grey matter of thespinal cord, and with a similar role the medullarycaudalis nucleus of the trigeminal system, are thoseregions predominantly involved in the reception,processing and rostral transmission of nociceptiveinformation (24, 75, 76, 90, 91). Within the dorsalhorn, all neurons possess receptive fields which areorganized in a somatotopic manner (93). Tissuedamage as well as peripheral nerve injury may causean expansion of dorsal horn receptor fields, therebymimicking an increase in peripheral input. Based onthe existence of inhibitory and excitatory intrinsicneurons, with either inter- or intralaminar, inter- orintrasegmental distribution, the dorsal horn consti-tutes a major station for the integration and modula-tion of all peripheral afferent signals, noxious andinnocuous, and, depending of the profile of the lat-ter, amplification or attenuation of nociceptive infor-mation may occur. Particular projection neuronstransfer the processed sensory information to su-praspinal destinations. Glutamate or aspartate hasbeen considered being the main transmitter of exci-tatory interneurons, but also vasoactive intestinalpeptide (VIP), SP, cholecystokinin (CCK) and neuro-tensin have been identiefied in enhancing nocicep-tive nervous traffic (29). To the contrary, inhibitoryinterneurons importantly counteract the flow of

nociceptive signals. Gamma-amino-butyric acid(GABA), a major inhibitory transmitter in the CNS,is localized in high concentration in interneurons oflaminae IIII, among others also in islet cells(Fig. 2), and has been implicated in the inhibition ofacute and persistent pain (64, 89). However, becauseNO also acts as a crucial transmitter in models forpersisting pain, co-localization of GABA with NOS,as it occurs in islet cells, may suggest even oppositefunctions for these neurons (2). Colocalization ofGABA with acetylcholine, enkaphalin, or glycine indifferent subpopulations of dorsal horn interneuronsconstitute a further modulatory principle of nocicep-tion. In addition, an antinociceptive role has beenattributed to cholinergic interneurons, acting viamuscarinic and nicotinic receptors, and to opioider-gic interneurons containing enkephalins or dynor-phin, which exert their actions via l-, d- and j-opioid receptors (29, 41, 77).

NMDA receptors, NO, and opioid receptors

The NMDA and opioid receptor systems are re-garded as the most important structures in nocicep-tion and antinociception; in addition, by comparisonof their distribution patterns a close relationship be-tween opioid receptors and NMDA receptors in


Fig. 2 Hypothetical mechanism of action of NO on peptide-containing pri-mary afferent C fibers involved in central sensitization. Stimulation of Adfibers activates via glutamate in islet cells the NMDA-NO cascade. NO dif-

fuses throughout lamina II and enhances the release of SP or CGRP form Cfibers. From (2), with permission


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many regions of the CNS has been found (67).Opioid receptors are synthesized within peripheralnociceptive neurons and transported to both the pe-ripheral and central endings of these fibers. Both,opioid and NMDA receptors have a major represen-tation in the dorsal horn, particularly within laminaII, suggesting a close functional relationship between

these two classes of transmitters. Evidence for a co-localization ofl-opioid and NMDA receptors in bothpre- and postsynaptic sites supports such a conclu-sion (47). Numerous studies have shown that opioidsdirectly or indirectly modulate NMDA receptor-mediated electrophysiological events within the CNS.Among the three subtypes of opioid receptors, l andd have either inhibited or potentiated NMDA recep-tor-mediated electrophysiological events (25, 97, 106,112), while j opioids by directly interacting with theNMDA receptor per se antagonized NMDA receptor-mediated currents (14, 26). However, although upre-gulation of the j opioid peptide dynorphin in the

dorsal horn has been detected in inflammation, itwas associated with either enhancement or reductionof nociceptive transmission at the spinal levels. Akey factor in determining the potency of spinalopioid receptors, particularly of the l subtype, ap-pears to be the spinal level of CCK, which potentlyreduces spinal l opioid actions (100). The inhibitionof opioids on Ca2+ channel activity of the NMDA re-ceptor suggests that they may act rather by regulat-ing intracellular events following NMDA receptoractivation. Besides PKC (7, 68), this affects two othercalcium-calmodulin dependent targets, NOS withNO, and phosholipase A2 with mobilization of ara-chidonic acid and prostaglandin formation (13, 30).Evidence that NO might be formed also in the brainis a recent finding (45). Although only a few percentof the neurons of the brain stain for NOS, their neu-ronal processes ramify so extensively that it is likelythat nearly every neuron in the brain is exposed toNO. In 1989, Bredt and Snyder discovered that theexcitatory transmitter glutamate acting at the NMDAsubtype of glutamate receptor generates NO forma-tion (16, 17). This is achieved in that glutamateopens the Ca2+ ion channel of this NMDA receptorand the elevation of intracellular calcium activatesNOS (94). NO as a gaseous molecule easily diffusesout from the neuron to act on neighboring nerveendings and astrocyte processes, and functions suchas a neurotransmitter (98). Because of its high affini-ty to guanylyl cyclase, NO stimulates the formationof cGMP in neurons. Most of the physiological ef-fects of cGMP are mediated by its intrinsic targetmolecule, the cyclic GMP-dependent protein kinase(PKG), which plays a central role in regulating cGMPsignaling in neurons, including such functions asmodulation of neurotransmitter release, gene expres-

sion, learning and memory (92, 107). Though NO,on the one hand, amplifies neuronal activities viacGMP pathways, it acts, on the other, as a negativefeedback regulator of NMDA receptor activity, pro-viding, thus, a subtle control on NOS-containingneurons to prevent overstimulation by glutamate.The structure involved is the so-called redox-modu-

latory site of the NMDA receptor which contains vic-inal sulfhydryl (thiol) groups which in their reducedstate allow Ca2+ influx, but prevent Ca2+ influx aftertheir oxidation to disulfides (3, 63, 96, 99). NO may,however, exert its inhibitory effect on NMDA re-sponses not only via the thiol redox site but mayalso modify intraneuronal Ca2+ homeostasis directly(53). The redox-modulatory site of the NMDA recep-tors has been successfully modified with thiol reduc-tants like dithiothreitol (63), dihydrolipoic acid orcysteine (56, 87), while oxygen-derived radicals andoxidized glutathione depressed NMDA-induced re-sponses (101, 102). In the superficial dorsal horn,

NO synthesis linked to NMDA receptor activationhas been implicated in the maintenance of hyperal-gesia in several models of persistent pain (73). Nu-merous studies have demonstrated that the release ofCGRP and SP is increased in the dorsal horn duringhyperalgesia, and that the NMDA-NO cascade is in-itiated by prolonged release of SP and glutamatefrom primary afferents (72, 84). Sodium nitroprus-side, a NO donor, evokes the release of CGRP andSP from dorsal horn slices (44), while thermal hy-peralgesia can be blocked by the NO inhibitor Nx-nitro-L-arginine methyl ester, L-NAME (84). Both,the development and expression of thermal hyperal-gesia are mediated through activation of NMDA re-ceptors (69). It has been hypothesized, therefore,that NO, released from islet cells upon activation byAd fibers, diffuses throughout lamina II and en-hances the release of SP and CGRP from C-fiberterminals (2), representing such one mechanism ofcentral sensitization (Fig. 2). However, because of co-existence of GABA in large islet cells, an inhibitorycounteraction on nociceptive traffic and, hence, onthe development of spinal hyperexcitability, has tobe considered. There is general agreement that hy-peralgesia and allodynia are induced, at least in part,by the development of spinal hyperexcitability. Thisphenomenon was first described by Mendell andWall (74) as windup and it is most likely that itdevelops selectively by increased C fiber activitywith concomitant release of their co-transmitters NKand SP in the dorsal horn, which qualitatively alterthe postsynaptic effects of glutamate or aspartate(105). The amplitude and duration of the windup isdepressed by NMDA and NK receptor antagonists.Thus, under conditions of chronic hyperalgesis, theinteraction between NK, especially NK1 and NMDA



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receptors would play the major role in determininghyperexcitability in the spinal cord. Boxall et al. (15)recently reported an early gene expression in spinalcord during ultraviolet irradiation induced peripher-al inflammation. As shown by the image analysis ofchanges in metabotropic glutamate receptor 3(mGluR3) mRNA in Fig. 3, there is an increase inmGluR3 mRNA expression at least for two days postunilateral hindpaw irradiation almost exclusively inthe dorsal horn of the appropriate lumbar segmentsof the spinal cord, with the highest density in lami-na II and III, however, on both sides of the spinalcord. There was a strong coincidence of the upregu-lation of mGluR3 mRNA with the development ofmechanical hyperalgesia and allodynia. Although theprecise role of changes in mGluR3 mRNA expressionduring hyperalgesis is not known, Boxall et al. (15)considered that mGluR activation, in general, couldenhance the activity of the ionotropic excitatoryamino acid receptors, which are the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)receptors, kainat and NMDA receptors.

Second-order nociceptive neurons

The second-order nociceptive neurons, with theircell bodies in the dorsal horn and their axon termi-

nation in the thalamus, are mainly of two types:those that respond to gentle stimuli and increasetheir responses when the stimuli become intense areclassified as wide-dynamic-range neurons, and thosethat respond exclusively to noxious stimuli are clas-sified as nociceptive-specific neurons (10). Althoughmany transmitters, including SP and CCK, are in-volved in carrying nociceptive information from thespinothalamic tract to the thalamus, and from thespinomesencephalic tract to the periaqueductal grey,numerous studies have shown that the most power-ful system in nociception is the NMDA receptor sys-tem. Recent studies have shown, however, that be-sides the classic spinothalamic tract of nociceptionmultiple other ascending pathways innervate notonly the thalamus, but also the amygdala, the stria-tum, nucleus accumbens, hypothalamus and septum,as well as the frontal, orbital cingulate, and infralim-bic cortex may also be directly accessed by spinalnociceptive neurons (19, 46, 54, 82). Although thereis no absolute clear anatomical separation in the as-cending nociceptive transfer systems to the suprasp-inal targets by which the global sensation of pain isfinally modulated and experienced, two dimensionsof pain can be distinguished: the sensory-discrimi-native, and the affective-cognitive component. Theformer deals with the perception and detection ofnoxious stimuli per se depending on their intensity,location, duration, temporal pattern and quality, the


Fig. 3 Image analysis of changes in mGluR3 mRNA expression during thecourse of UV-induced hyperalgesia in rats. A: control, B: one day, C: twodays, D: three days after UV irradiation. The pseudocolors cover all grey

values representing significant expression (red-yellow: maximum, green-blue:minimum). Scale bar = 200 lm. From (15), with permission


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latter comprises the relationship between pain andmood, the attention to and memory of pain, the ca-pacity to cope with and tolerate pain and its rationa-lization (31, 78). The thalamus, subdivided in var-ious nuclei, is still considered as the crucial relay forthe reception and processing of nociceptive informa-tion en route to the cortex (20). Whereas integration

of sensory-discriminative nociceptive input can beallocated mainly to posterior thalamic nuclei, inputfrom visceral tissues to the thalamus is, in general,not topographically organized (23).

Third-order nociceptive neurons

Various approaches are used to investigate the path-way of nociceptive information from the thalamus tothe cortex. Particularly metabolic and cerebral bloodflow imaging techniques have revealed that the so-

matosensory area (S-I) is only one among manyother circumscribed cortical areas which are impli-cated in the global experience of pain. Recently, thesomatosensory area II (S-II), several regions of theinferior and anterior parietal cortex, the insular cor-tex, the anterior cingulate cortex and the medial pre-frontal cortex have been identified as being consis-

tently activated by cutaneous and intramuscular nox-ious stimulation (21, 22, 34, 71). It is possible thatapart from a direct thalamocortical projection someof the cortical areas, constituting a complex patternof connections among themselves, may be also indi-rectly activated via various limbic structures.Whereas activation of area S-I is almost exclusivelycontralaterally detected following noxious stimula-tion, in line with a pain-localizing and discrimina-tive-sensory function of this area, the affective-cog-nitive aspects of pain have been attributed to area S-II, the cingulate, inferior parietal, prefrontal and in-sular cortex. As illustrated in Fig. 4, females, exhibit-


Fig. 4 Statistical map of regional cerebral blood flow responses of 10 males(M) and 10 females (F) to repetitive noxious heat stimulation (50 8C) of theleft volar forearm. Color coding of Z scores as indicated by flame bar atright. The right hemisphere of the MRI stereotactic template is on the read-ers left. The numbers below columns of images indicate millimeters above aplane connecting the anterior and posterior commissures. Significant activa-tions occur in the contralateral cingulate cortext (+41, +37), premotor, andinsular cortex (+15, +7), ipsilateral insula (+7, +15), and bilateral cerebellar

vermis (12). Structures significantly activated in males were contralateralprefrontal cortex (+52), anterior insula (+2), thalamus (+15), ipsilateral lenti-cular nucleus (+2), contralateral cerebellum (25). Structures significantlyactivated in females were contralateral prefrontal cortex (+32), anterior insula(+2), thalamus (+15), ipsilateral lenticular nucleus (+2), contralateral cerebel-lum (25). Significant differences between males and females occurred incontralateral thalamus, anterior insula and prefrontal cortex. From (21), withpermission


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ing no difference in pain thresholds, react to nox-ious cutaneous stimulation with a distinctly differentpattern of cortical activation and a significantlygreater activation of the contralateral prefrontal cor-tex compared with males (21). Whether this genderdifference can be related to diseases with musculo-skeletal pain of undefined origin, like fibromyalgia

and which occurs mainly in females, awaits furtherelucidation.

Antinociception

It is a generally accepted view that noxious stimulisignal tissue injury or, in a broader sense, the loss ofhomeostasis, either locally or systemically. It seems,therefore, plausible to consider the restoration ofhomeostasis and the induction of analgesia as amain function of the nociceptive system, besides of

the obvious importance of pain in survival. Nocicep-tive signals have been found to be modulated at anylevel of the brain giving the impression of the exis-tence of a hierarchically organized antinociceptivesystem (8, 50). Pain modulation is a behaviorallysignificant physiological process, using a discreteCNS network involving release of opioid peptides,biogenic amines and other transmitters.

It appears from many studies that the strongestantinociception occurs at that the level where theprimary nociceptors end, which is the dorsal hornof the spinal cord. Activation of GABAergic inter-neurons, or mimicking their activity by GABAB re-ceptor agonist baclofen reduces the release of gluta-mate, SP and CGRP from nociceptive afferents (64).The concentration of GABA is the highest in thedorsal horn of the spinal cord. The dense distribu-tion within the dorsal horn, especially lamina I andII, of benzodiazepine (GABA-A1a) and opioid recep-tors underlines the capacity of these regions in mod-ulating nociception leading to total spinal analgesiain response to strong nociceptive input (43, 64, 65).The intraspinal antinociceptive circuits only extenda few segments from the level at which they are en-gaged.

Less intense noxious stimuli can activate thesespinal antinociceptive circuits via serotonergic andnoradrenergic projections descending from the nu-clei in the rostral ventro-medial medulla (50, 108111). The extent to which antinociceptive mecha-nisms in the dorsal horn are activated may dependcritically on environmental events which are consid-ered as aversive or stressful, or are elicited by innatedanger signals (39, 40).

Several studies have provided evidence that suchconditionally antinociceptive responses are mediated

by opioid and GABAergic mechanisms in the peria-queductal grey, which projects via glutamatergic des-cending pathways to the rostral ventro-medial me-dulla and activates there the descending antinocicep-tive serotonergic and noradrenergic pathways to thespinal dorsal horn (51). The periaqueductal grey ispivotally located to transmit cortical and diencepha-

lic inputs to the lower brainstem. Retrograde studieshave established that the periaqueductal grey re-ceives significant inputs from the frontal and insularcortex, the amygdala, and the hypothalamus (5, 8).Learned or innate danger signals mediated via theamygdala to the periaqueductal grey with its intrin-sic GABAergic and opioid receptors seems to consti-tute a neuronal network engaged in the central sen-sitization of antinociception. Recent studies havedisclosed for the periaqueductal grey a high degreeof anatomical and functional organization with lon-gitudinal subdivisions in a lateral and a ventrolateralcolumn. Coordinated patterns of skeletal, autonomic

and antinociceptive adjustments have been elicitedwhich appear to be triggered by discrete cortical in-puts, the medial preoptic area, and the central nu-cleus of the amygdala (5). It was found that deep so-matic noxious stimuli from muscle, joints or the vis-cera preferentially activated the ventrolateral peria-queductal grey, whereas cutaneous noxious stimula-tion activated the lateral column. Experimental exci-tation of the ventrolateral column evoked cessationof spontaneous activity, hyporeactivity, hypotension,bradycardia, associated with opiod analgesia, resem-bling the reaction pattern following injury, or afterdefeat in a social encounter. Activation of the lateralcolumn produced a confrontational defensive reac-tion, either a fight or a flight response, hypertension,tachycardia, associated with non-opioid analgesia viaactivation in the lower brainstem of the descendingserotonergic and noradrenergic antinociceptive path-ways. The medial preoptic area is strongly impli-cated in temperature regulation and sleep receivingthermal signals from the body core (86) and the skin(52) and projects predominantly to the ventrolateralcolumn of the periaqueductal grey (5). It has beenshown that inescapable shock which functionallyparalleles the experimental activation of the ventro-lateral periaqueductal grey is associated with hy-perthermia resembling fever (35). Whether the riseof body temperature which almost always accompa-nies pain rests on these pathways has to be eluci-dated.

Pain, and any kind of stress, whether psychologi-cal, infectious or traumatic, activates corticotropin-releasing hormone (CRH) neurons (27, 32). Sincestress induced activation of the hypothalamic-pitui-tary axis has been shown to produce analgesia (4),the analgesia induced was considered to be due pri-



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marily to the release of b-endorphin (38). Recently,however, it was shown that CRH can act at all levelsof the neuraxis to produce analgesia, which is not de-pendent on the release ofb-endorphin (61). Interest-ingly, inflammation must be present for local CRHto evoke analgesia. The specificity of the effects ofCRH on tonic pain suggests that CRH may preferen-

tially play a role in prolonged clinical pain. Recent ex-periments performed by Timpl et al. (104) have con-firmed that the absence of the CRH receptor 1 (Crhr1)in specific areas of the brain distinctly diminishes thephysiological response of the organism to a stressfulstimulus. These results imply strongly that Crhr1 isthe receptor that mediates the response to stress.

The precise role of the cortex and its projectionto structures involved in antinociception is less clear.It is evident that the area S-I, thalamus and otherhigher centers do not merely behave as passive re-cipients and relayers of information from the dorsalhorn. Rather, they are themselves involved in the

further integration of adaptive, neuronal changes inacute and chronic painful states due to either in-flammation or peripheral nerve damage (95). Corti-cal areas have been found to undergo a considerablereorganization of their receptive fields in patientssuffering from phantom limb pain, showing shifts ofthe cortical areas adjacent to the amputation zonetowards the representation of the deafferented bodypart (80). Stimulation of area S-II has been found toproduced a weak antinociceptive behavioral re-sponse, which was remarkably potentiated by sys-temic administration of an NOS blocker (58). Allthree opioid receptor types have been identified insuch regions as the deep layers of the parietal, tem-

poral and occipital cortex, and particularly activa-tion of opioid receptors in the anterior cingulate cor-tex can produce powerful antinociception (62, 66).

Pain as a multidimensional experience comprisesnot only motivational, affective and cognitive com-ponents, but also most often a locomotor response.Nociceptive information has been found to reach the

basal ganglia through several afferent sources includ-ing the cerebral cortex, from area S-II, the prefrontalcortex, and the anterior cingulate cortex (28). Multi-ple neuronal loops transmitting nociceptive informa-tion connected with the cerebral cortex, the basalganglia and thalamus may provide a mechanism thatregulates ascending nociceptive signals. Opioids pro-duce markedly different effects on locomotion, withl- and d-receptor agonists increasing locomotion,and j-receptor agonists decreasing locomotion.These pharmacological differences appear to corre-late with the effects of opioids on nigrostriatal re-lease of dopamine, where l- and d-receptor agonists

increase, and j-receptor agonists decrease, striatalrelease of dopamine (36, 81). The basal ganglia donot participate in the spatial localization of pain. Pa-tients with basal ganglia disease (Parkinsons disease,Huntingtons disease) complain of pain that involveslarge areas of their body and that is difficult to loca-lize in punctate areas. What can be deduced fromthe expression of the various patterns of pain ex-perience is that pain develops not along rigid path-ways from a defined peripheral location to definedareas of the cortex, but merely discloses the plasti-city of the nervous system or the wisdom of thebody to preserve homeostasis in a noxious environ-ment.


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