Z Rheumatol 60:404–415 (2001)
`© Steinkopff Verlag 2001
`
`MAIN TOPIC
`
`W. Riedel
`G. Neeck
`
`Nociception, pain, and antinociception:
`current concepts
`
`ZfRh 347
`
`nociception occurs at all levels of
`the neuraxis, thus, eliciting the
`multidimensional experience of
`pain involving sensory-discrimi-
`native, affective-motivational,
`cognitive and locomotor compo-
`nents.
`
`n Zusammenfassung Die Physio-
`logie der Schmerzwahrnehmung
`beruht auf einer komplexen Inter-
`aktion peripherer, spinaler und
`supraspinaler Strukturen des Zen-
`tralnervensystems (ZNS). Auf je-
`der Ebene des ZNS erfolgt eine
`Modulation nozizeptiver Informa-
`tion, wobei die zwei wichtigsten
`Transmittersysteme der Nozizepti-
`on und der Antinozizeption, das
`N-methyl-D-aspartate (NMDA)-
`und das Opioid-Receptor System,
`eine nahezu identische Verteilung
`zeigen. Glutamat, der natürliche
`exzitatorische Transmitter aller
`Neurone mit ionotropen NMDA-
`Rezeptoren, bewirkt durch Öffnen
`des Ca2+-Kanals über die damit
`verbundene Aktivierung der in-
`traneuronalen Stickoxidsynthase
`die Freisetzung von Stickoxid
`(NO). Diffusion des NO in Nach-
`barneurone erhöht deren cGMP-
`Synthese verbunden mit einer er-
`höhten neuronalen Aktivität, wel-
`che sich als Hyperalgesie oder Al-
`lodynie äußert, wenn Transmitter
`aus nozizeptiven Nervenendigun-
`gen freigesetzt werden. Die peri-
`phere Sensibilisierung nozizepti-
`
`methyl-D-aspartate (NMDA) and
`opioid receptor system, show a
`close distribution pattern in nearly
`all CNS regions, and activation of
`NMDA receptors has been found
`to contribute to the hyperalgesia
`associated with nerve injury or
`inflammation. Apart from sub-
`stance P (SP), the major facilita-
`tory effect in nociception is ex-
`erted by glutamate as the natural
`activator of NMDA receptors.
`Stimulation of ionotropic NMDA
`receptors causes intraneuronal
`elevation of Ca2+ which stimulates
`nitric oxide synthase (NOS) and
`the production of nitric oxide
`(NO). NO as a gaseous molecule
`diffuses out from the neuron and
`by action on guanylyl cyclase, NO
`stimulates in neighboring neurons
`the formation of cGMP. Depending
`on the expression of cGMP-con-
`trolled ion channels in target
`neurons, NO may act excitatory or
`inhibitory. NO has been implicated
`in the development of hyperexcit-
`ability, resulting in hyperalgesia or
`allodynia, by increasing nocicep-
`tive transmitters at their central
`terminals. Among the three sub-
`types of opioid receptors, l- and d-
`receptors either inhibit or po-
`tentiate NMDA receptor-mediated
`events, while j opioids antagonize
`NMDA receptor-mediated activity.
`Recently, CRH has been found to
`act at all levels of the neuraxis to
`produce analgesia. Modulation of
`
`Nozizeption, Schmerz und
`Antinozizeption
`
`n Summary The physiology of
`nociception involves a complex
`interaction of peripheral and cen-
`tral nervous system (CNS) struc-
`tures, extending from the skin, the
`viscera and the musculoskeletal
`tissues to the cerebral cortex. The
`pathophysiology of chronic pain
`shows alterations of normal phys-
`iological pathways, giving rise to
`hyperalgesia or allodynia. After
`integration in the spinal cord, no-
`ciceptive information is trans-
`ferred to thalamic structures be-
`fore it reaches the somatosensory
`cortex. Each of these levels of the
`CNS contain modulatory mecha-
`nisms. The two most important
`systems in modulating nocicep-
`tion and antinociception, the N-
`
`W. Riedel ())
`Max-Planck-Institut für physiologische
`und klinische Forschung
`W.-G.-Kerckhoff-Institut
`Parkstraße 1
`61231 Bad Nauheim, Germany
`
`G. Neeck
`Stiftung W. G. Kerckhoff
`Herz- und Rheumazentrum
`Abteilung Rheumatologie
`Ludwigstraße 37–39
`61231 Bad Nauheim, Germany
`
`

`

`W. Riedel and G. Neeck
`Nociception, pain, and antinociception: current concepts
`
`405
`
`n Key words Nociception –
`glutamate – NMDA – nitric oxide –
`sensitization – opioids –
`spinal cord – brainstem –
`cerebral cortex – pain –
`periaqueductal grey –
`basal ganglia –
`descending antinociception
`
`n Schlüsselwörter Nozizeption –
`Glutamat – NMDA – Stickoxid –
`Sensibilisierung –
`Opioide – Rückenmark –
`Hirnstamm – Kortex – Schmerz –
`zentrales Höhlengrau –
`Basalganglien – deszendierende
`Antinozizeption
`
`ver Axone erfolgt meist über Se-
`rotonin, Bradykinin oder Prosta-
`glandine. Während die l- und d-
`Opioid-Rezeptoren die NMDA-Re-
`zeptor vermittelte Nozizeption
`hemmen oder verstärken, antago-
`nisieren j-Opioide NMDA-Rezep-
`tor vermittelte Reaktionen voll-
`ständig. Hingegen wirkt Cortico-
`tropin-relasing-Hormon auf allen
`Ebenen des ZNS antinozizeptiv.
`
`Introduction
`
`The integrity of all living organisms is guaranteed
`by interaction of two highly specialized systems: the
`immune 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 immediately
`alerts the organism to the presence of damaging
`stimuli. 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 sharing
`common 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 the
`word through experiences related to injury in early
`life“ (79). Pain is not homogeneous and comprises
`three categories: physiological,
`inflammatory, and
`neuropathic 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 because
`powerful antinociceptive mechanisms are simulta-
`neously turned on by the noxious stimulus. Chronic
`pain is frequently associated with degenerative tissue
`diseases such as rheumatoid arthritis, does not
`spontaneously resolve and serves no obvious useful
`biological function (70), and it may be that for that
`reason genes favoring an opposing force to chronic
`pain have not been developed during evolution.
`
`Physiological pain
`
`Physiological pain is initiated with the generation of
`action potentials of specialized sensory nociceptor fi-
`bers innervating peripheral tissues. The action poten-
`tials transmitting somatic pain are conducted to the
`CNS 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 ganglion
`end in the dorsal horn of the spinal cord, the trigem-
`inal nociceptors in the trigeminal sensory nuclei of the
`brainstem, and synapse there with the second-order
`neurons, which axons ascend in the spinothalamic
`tract to the thalamus. The third-order neurons project
`to the postcentral gyrus of the cerebral cortex, where
`information is somatotopically organized. Most noci-
`ceptive signals originating from visceral organs reach
`the 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 that
`use an inensity-encoding mechanism (23, 49). Visceral
`nociceptive messages are conveyed to the spinal cord
`by relatively few visceral afferent fibers which activate
`many 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 visceral
`stimulation are needed to activate viscero-somatic
`neurons, most of which can also be excited by noxious
`stimulation of their somatic receptive fields. Thus, vis-
`ceral pain is the consequence of a diffuse activation of
`somato-sensory nociceptive systems which prevents
`accurate spatial discrimination or localization of the
`stimuli. Although a specific ascending pathway for vis-
`ceral nociception has not been found, projection of
`viscero-somatic neurons include the spino-reticular
`and 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
`
`

`

`406
`
`Zeitschrift für Rheumatologie, Band 60, Heft 6 (2001)
`© Steinkopff Verlag 2001
`
`system with alien matter. Neuropathic pain, caused
`by either peripheral or central nervous system le-
`sions, is the most common form of opioid-poorly-re-
`sponsive pain. Both forms of pain are characterized
`by hypersensitivity at the site of damage and in ad-
`jacent normal tissue. Allodynia, either mechanical or
`thermal, arises from stimuli which never normally
`cause pain, while greater and prolonged pain result-
`ing from noxious stimuli manifests itself as hyperal-
`gesia.
`
`acids glutamate and aspartate, substance P (SP) and
`calcitonin gene-related peptide (CGRP) have been
`found in the superficial dorsal horn and are, there-
`fore, considered as the main nociceptive transmitters
`under physiological conditions, while various other
`transmitters, colocalized and expressed in both sets
`of nociceptive afferents, seem to be mainly elevated
`under pathological conditions including their recep-
`tors.
`
`First-order nociceptive neurons
`
`The sensation of pain that is experienced arrives in
`the 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 nociceptors
`form two classes: myelinated A d mechanoreceptor
`and 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 some
`Ad 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
`
`[II[] Aa-6 cutaneous
`
`(sensitive)
`
`~ A6 !Group Ill)
`
`nociceptive
`
`• C !Group IV)
`
`D Group I muscle
`~ Group II muscle
`
`Fig. 1 Distribution of cutaneous and muscle afferent fibers to spinal grey
`matter
`
`Peripheral sensitization
`
`Nociceptor sensitization underlies the phenomenon
`of peripheral hyperalgesia that results in an increase
`in the perception of and response to pain. Several
`mechanisms have been proposed to account for hy-
`peralgesia including direct activation of nociceptors
`as well as sensitization of nociceptors through the
`production 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 by
`pathophysiological stimuli, appear to be implicated
`in the etiology of a number of pain conditions, asso-
`ciated with inflammation and rheumatoid diseases.
`Most actions of BK, including the acute activation of
`pain, are mediated through the membrane-bound B2
`receptor, coupled with a G protein. B2 receptors have
`been localized to nociceptive nerve terminals in
`skin, 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 thereby
`neuronal 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 neuronal
`membrane (57). The activation of sensory fibers by
`BK also causes the release of neuropeptides such as
`SP, neurokinin A (NKA) and CGRP (6). In a recipro-
`cal
`fashion, however, prostaglandins can sensitize
`nociceptors, Ad as well as C fibers, to the action of
`BK, 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, the
`dorsal horn contains various other neuropeptides
`originating from neurons intrisic to the dorsal horn,
`
`

`

`W. Riedel and G. Neeck
`Nociception, pain, and antinociception: current concepts
`
`407
`
`Clibers - -,-----
`~
`·------
`
`lamina I
`
`diffusion of NO
`
`---- -
`t t
`t
`
`- - - - - - - -
`
`- -
`
`- - -
`
`Islet cell
`
`t
`
`- -
`
`---
`
`--
`
`Lamina II
`..........
`
`.
`
`Lamina I\
`
`....
`
`Fig. 2 Hypothetical mechanism of action of NO on peptide-containing pri-
`mary afferent C fibers involved in central sensitization. Stimulation of A d
`fibers 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 C
`fibers. From (2), with permission
`
`or from descending axon terminals of neurons with
`cell bodies located in the brainstem (11, 12). The
`laminae I, II, V, VI and X of the grey matter of the
`spinal cord, and with a similar role the medullary
`caudalis nucleus of the trigeminal system, are those
`regions predominantly involved in the reception,
`processing and rostral transmission of nociceptive
`information (24, 75, 76, 90, 91). Within the dorsal
`horn, all neurons possess receptive fields which are
`organized in a somatotopic manner (93). Tissue
`damage as well as peripheral nerve injury may cause
`an expansion of dorsal horn receptor fields, thereby
`mimicking an increase in peripheral input. Based on
`the existence of inhibitory and excitatory intrinsic
`neurons, with either inter- or intralaminar, inter- or
`intrasegmental distribution, the dorsal horn consti-
`tutes a major station for the integration and modula-
`tion of all peripheral afferent signals, noxious and
`innocuous, and, depending of the profile of the lat-
`ter, amplification or attenuation of nociceptive infor-
`mation may occur. Particular projection neurons
`transfer the processed sensory information to su-
`praspinal destinations. Glutamate or aspartate has
`been considered being the main transmitter of exci-
`tatory interneurons, but also vasoactive intestinal
`peptide (VIP), SP, cholecystokinin (CCK) and neuro-
`tensin have been identiefied in enhancing nocicep-
`tive nervous traffic (29). To the contrary, inhibitory
`interneurons
`importantly counteract
`the flow of
`
`acid
`signals. Gamma-amino-butyric
`nociceptive
`(GABA), a major inhibitory transmitter in the CNS,
`is localized in high concentration in interneurons of
`laminae I–III, among others also in islet cells
`(Fig. 2), and has been implicated in the inhibition of
`acute and persistent pain (64, 89). However, because
`NO also acts as a crucial transmitter in models for
`persisting pain, co-localization of GABA with NOS,
`as it occurs in islet cells, may suggest even opposite
`functions for these neurons (2). Colocalization of
`GABA with acetylcholine, enkaphalin, or glycine in
`different subpopulations of dorsal horn interneurons
`constitute a further modulatory principle of nocicep-
`tion. In addition, an antinociceptive role has been
`attributed to cholinergic interneurons, acting via
`muscarinic 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 comparison
`of their distribution patterns a close relationship be-
`tween opioid receptors and NMDA receptors in
`
`

`

`408
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`Zeitschrift für Rheumatologie, Band 60, Heft 6 (2001)
`© Steinkopff Verlag 2001
`
`the CNS has been found (67).
`many regions of
`Opioid receptors are synthesized within peripheral
`nociceptive 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 lamina
`II, suggesting a close functional relationship between
`these two classes of transmitters. Evidence for a co-
`localization of l-opioid and NMDA receptors in both
`pre- and postsynaptic sites supports such a conclu-
`sion (47). Numerous studies have shown that opioids
`directly or
`indirectly modulate NMDA receptor-
`mediated electrophysiological events within the CNS.
`Among the three subtypes of opioid receptors, l and
`d have either inhibited or potentiated NMDA recep-
`tor-mediated electrophysiological events (25, 97, 106,
`112), while j opioids by directly interacting with the
`NMDA 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, it
`was associated with either enhancement or reduction
`of nociceptive transmission at the spinal
`levels. A
`key factor in determining the potency of spinal
`opioid receptors, particularly of the l subtype, ap-
`pears to be the spinal level of CCK, which potently
`reduces spinal l opioid actions (100). The inhibition
`of opioids on Ca2+ channel activity of the NMDA re-
`ceptor suggests that they may act rather by regulat-
`ing intracellular events following NMDA receptor
`activation. Besides PKC (7, 68), this affects two other
`calcium-calmodulin dependent
`targets, NOS with
`NO, and phosholipase A2 with mobilization of ara-
`chidonic acid and prostaglandin formation (13, 30).
`Evidence that NO might be formed also in the brain
`is a recent finding (45). Although only a few percent
`of the neurons of the brain stain for NOS, their neu-
`ronal processes ramify so extensively that it is likely
`that nearly every neuron in the brain is exposed to
`NO. In 1989, Bredt and Snyder discovered that the
`excitatory transmitter glutamate acting at the NMDA
`subtype of glutamate receptor generates NO forma-
`tion (16, 17). This is achieved in that glutamate
`opens the Ca2+ ion channel of this NMDA receptor
`and the elevation of intracellular calcium activates
`NOS (94). NO as a gaseous molecule easily diffuses
`out from the neuron to act on neighboring nerve
`endings and astrocyte processes, and functions such
`as a neurotransmitter (98). Because of its high affini-
`ty to guanylyl cyclase, NO stimulates the formation
`of cGMP in neurons. Most of the physiological ef-
`fects of cGMP are mediated by its intrinsic target
`molecule, the cyclic GMP-dependent protein kinase
`(PKG), which plays a central role in regulating cGMP
`signaling in neurons,
`including such functions as
`modulation of neurotransmitter release, gene expres-
`
`sion, learning and memory (92, 107). Though NO,
`on the one hand, amplifies neuronal activities via
`cGMP pathways, it acts, on the other, as a negative
`feedback regulator of NMDA receptor activity, pro-
`viding,
`thus, a subtle control on NOS-containing
`neurons 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 reduced
`state allow Ca2+ influx, but prevent Ca2+ influx after
`their 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 may
`also 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 or
`cysteine (56, 87), while oxygen-derived radicals and
`oxidized glutathione depressed NMDA-induced re-
`sponses (101, 102). In the superficial dorsal horn,
`NO synthesis linked to NMDA receptor activation
`has been implicated in the maintenance of hyperal-
`gesia in several models of persistent pain (73). Nu-
`merous studies have demonstrated that the release of
`CGRP and SP is increased in the dorsal horn during
`hyperalgesia, and that the NMDA-NO cascade is in-
`itiated by prolonged release of SP and glutamate
`from primary afferents (72, 84). Sodium nitroprus-
`side, a NO donor, evokes the release of CGRP and
`SP 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 by
`Ad fibers, diffuses throughout lamina II and en-
`hances the release of SP and CGRP from C-fiber
`terminals (2), representing such one mechanism of
`central sensitization (Fig. 2). However, because of co-
`existence of GABA in large islet cells, an inhibitory
`counteraction on nociceptive traffic and, hence, on
`the development of spinal hyperexcitability, has to
`be considered. There is general agreement that hy-
`peralgesia and allodynia are induced, at least in part,
`by the development of spinal hyperexcitability. This
`phenomenon was first described by Mendell and
`Wall (74) as „windup“ and it is most likely that it
`develops selectively by increased C fiber activity
`with concomitant release of their co-transmitters NK
`and SP in the dorsal horn, which qualitatively alter
`the postsynaptic effects of glutamate or aspartate
`(105). The amplitude and duration of the windup is
`depressed by NMDA and NK receptor antagonists.
`Thus, under conditions of chronic hyperalgesis, the
`interaction between NK, especially NK1 and NMDA
`
`

`

`W. Riedel and G. Neeck
`Nociception, pain, and antinociception: current concepts
`
`409
`
`Fig. 3 Image analysis of changes in mGluR3 mRNA expression during the
`course of UV-induced hyperalgesia in rats. A: control, B: one day, C: two
`days, 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
`
`receptors would play the major role in determining
`hyperexcitability in the spinal cord. Boxall et al. (15)
`recently reported an early gene expression in spinal
`cord during ultraviolet irradiation induced peripher-
`al inflammation. As shown by the image analysis of
`changes
`in metabotropic
`glutamate
`receptor
`3
`(mGluR3) mRNA in Fig. 3, there is an increase in
`mGluR3 mRNA expression at least for two days post
`unilateral hindpaw irradiation almost exclusively in
`the dorsal horn of the appropriate lumbar segments
`of the spinal cord, with the highest density in lami-
`na II and III, however, on both sides of the spinal
`cord. There was a strong coincidence of the upregu-
`lation of mGluR3 mRNA with the development of
`mechanical hyperalgesia and allodynia. Although the
`precise role of changes in mGluR3 mRNA expression
`during hyperalgesis is not known, Boxall et al. (15)
`considered that mGluR activation, in general, could
`enhance the activity of
`the ionotropic excitatory
`amino 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 their
`cell 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 increase
`their responses when the stimuli become intense are
`classified as wide-dynamic-range neurons, and those
`that respond exclusively to noxious stimuli are clas-
`sified as nociceptive-specific neurons (10). Although
`many transmitters, including SP and CCK, are in-
`volved in carrying nociceptive information from the
`spinothalamic tract to the thalamus, and from the
`spinomesencephalic 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 nociception
`multiple other ascending pathways innervate not
`only 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 spinal
`nociceptive neurons (19, 46, 54, 82). Although there
`is no absolute clear anatomical separation in the as-
`cending nociceptive transfer systems to the suprasp-
`inal targets by which the global sensation of pain is
`finally modulated and experienced, two dimensions
`of pain can be distinguished: the sensory-discrimi-
`native, and the affective-cognitive component. The
`former deals with the perception and detection of
`noxious stimuli per se depending on their intensity,
`location, duration, temporal pattern and quality, the
`
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`Zeitschrift für Rheumatologie, Band 60, Heft 6 (2001)
`© Steinkopff Verlag 2001
`
`latter comprises the relationship between pain and
`mood, 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 for
`the reception and processing of nociceptive informa-
`tion en route to the cortex (20). Whereas integration
`of sensory-discriminative nociceptive input can be
`allocated mainly to posterior thalamic nuclei, input
`from 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 to
`the cortex. Particularly metabolic and cerebral blood
`flow imaging techniques have revealed that the so-
`
`matosensory area (S-I) is only one among many
`other circumscribed cortical areas which are impli-
`cated in the global experience of pain. Recently, the
`somatosensory area II (S-II), several regions of the
`inferior 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 that
`apart from a direct thalamocortical projection some
`of the cortical areas, constituting a complex pattern
`of connections among themselves, may be also indi-
`rectly
`activated via
`various
`limbic
`structures.
`Whereas activation of area S-I is almost exclusively
`contralaterally 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-
`
`
`
`M ~ , • • • f ·' :~
`
`+52
`
`+41
`
`+37
`
`+32
`
`+15
`
`Ft,aooe 1
`MClll w:~
`. ... ,~~ I
`F ~ .·!'.~. -~ .
`~~- .~
`
`+7
`
`+2
`
`-7
`
`-12
`
`... ,1,
`-25
`
`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 the
`left volar forearm. Color coding of Z scores as indicated by flame bar at
`right. The right hemisphere of the MRI stereotactic template is on the read-
`er’s left. The numbers below columns of images indicate millimeters above a
`plane connecting the anterior and posterior commissures. Significant activa-
`tions occur in the contralateral cingulate cortext (+41, +37), premotor, and
`insular cortex (+15, +7), ipsilateral insula (+7, +15), and bilateral cerebellar
`
`vermis (–12). Structures significantly activated in males were contralateral
`prefrontal cortex (+52), anterior insula (+2), thalamus (+15), ipsilateral lenti-
`cular nucleus (+2), contralateral cerebellum (–25). Structures
`significantly
`activated 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 in
`contralateral thalamus, anterior insula and prefrontal cortex. From (21), with
`permission
`
`

`

`W. Riedel and G. Neeck
`Nociception, pain, and antinociception: current concepts
`
`411
`
`ing no difference in pain thresholds, react to nox-
`ious cutaneous stimulation with a distinctly different
`pattern of cortical activation and a significantly
`greater activation of the contralateral prefrontal cor-
`tex compared with males (21). Whether this gender
`difference can be related to diseases with musculo-
`skeletal pain of undefined origin, like fibromyalgia
`and which occurs mainly in females, awaits further
`elucidation.
`
`Antinociception
`
`It is a generally accepted view that noxious stimuli
`signal tissue injury or, in a broader sense, the loss of
`homeostasis, either locally or systemically. It seems,
`therefore, plausible to consider the restoration of
`homeostasis and the induction of analgesia as a
`main function of the nociceptive system, besides of
`the obvious importance of pain in survival. Nocicep-
`tive signals have been found to be modulated at any
`level of the brain giving the impression of the exis-
`tence of a hierarchically organized antinociceptive
`system (8, 50). Pain modulation is a behaviorally
`significant physiological process, using a discrete
`CNS network involving release of opioid peptides,
`biogenic amines and other transmitters.
`It appears from many studies that the strongest
`antinociception occurs at that the level where the
`primary nociceptors end, which is the dorsal horn
`of 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 the
`dorsal horn of the spinal cord. The dense distribu-
`tion within the dorsal horn, especially lamina I and
`II, of benzodiazepine (GABA-A1a) and opioid recep-
`tors underlines the capacity of these regions in mod-
`ulating nociception leading to total spinal analgesia
`in response to strong nociceptive input (43, 64, 65).
`The intraspinal antinociceptive circuits only extend
`a few segments from the level at which they are en-
`gaged.
`Less intense noxious stimuli can activate these
`spinal antinociceptive circuits via serotonergic and
`noradrenergic projections descending from the nu-
`clei in the rostral ventro-medial medulla (50, 108–
`111). The extent to which antinociceptive mecha-
`nisms in the dorsal horn are activated may depend
`critically on environmental events which are consid-
`ered as aversive or stressful, or are elicited by innate
`danger signals (39, 40).
`Several studies have provided evidence that such
`conditionally 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 the
`spinal dorsal horn (51). The periaqueductal grey is
`pivotally located to transmit cortical and diencepha-
`lic inputs to the lower brainstem. Retrograde studies
`have established that
`the periaqueductal grey re-
`ceives significant inputs from the frontal and insular
`cortex, the amygdala, and the hypothalamus (5, 8).
`Learned or innate danger signals mediated via the
`amygdala 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 have
`disclosed for the periaqueductal grey a high degree
`of anatomical and functional organization with lon-
`gitudinal subdivisions in a lateral and a ventrolateral
`column. Coordinated patterns of skeletal, autonomic
`and antinociceptive adjustments have been elicited
`which 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 cessation
`of spontaneous activity, hyporeactivity, hypotension,
`bradycardia, associated with opiod analgesia, resem-
`bling the reaction pattern following injury, or after
`defeat in a social encounter. Activation of the lateral
`column produced a confrontational defensive reac-
`tion,