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52 Manning, P.T. et al. (1987) MHC-specific cytotoxic T lymphocyte killing of dissociated sympathetic neuronal cultures. Am. J. Pathol. 128, 395–409 53 Medana, I. et al. (2001) Transection of major histocompatibility complex class I-induced neurites by cytotoxic T lymphocytes. Am. J. Pathol. 159, 809–815 54 Murray, P.D. et al. (1998) CD4(+) and CD8(+) T cells make discrete contributions to demyelination and neurologic disease in a viral model of multiple sclerosis. J. Virol. 72, 7320–7329 55 Murray, P.D. et al. (1998) Perforin-dependent neurologic injury in a viral model of multiple sclerosis. J. Neurosci. 18, 7306–7314 56 Noske, K. et al. (1998) Virus-specific CD4+ T cells eliminate borna disease virus from the brain via induction of cytotoxic CD8+ T cells. J. Virol. 72, 4387–4395 57 Akasaki, Y. et al. (2001) Antitumor effect of immunizations with fusions of dendritic and glioma cells in a mouse brain tumor model. J. Immunother. 24, 106–113 58 Walker, P.R. et al. (2000) The brain parenchyma is permissive for full antitumor CTL effector function, even in the absence of CD4 T cells. J. Immunol. 165, 3128–3135 59 Duan, W.M. et al. (1995) Temporal pattern of host responses against intrastriatal grafts of

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Chronic pain and medullary descending facilitation Frank Porreca, Michael H. Ossipov and G.F. Gebhart Chronic pain, whether the result of nerve trauma or persistent inflammation, is a debilitating condition that exerts a high social cost in terms of productivity, economic impact and quality of life. Currently available therapies yield limited success in treating such pain, suggesting the need for new insight into underlying mechanism(s). Here, we examine the likelihood that sustained activation of descending modulatory pathways that facilitate pain transmission could underlie some states of chronic pain. Such activation of descending facilitatory pathways might be the result of neuroplastic changes that occur at medullary sites in response to persistent input of pain signals. Understanding the mechanisms of descending facilitation and the spinal effects of such discharge could provide new insights into the modulation of chronic pain.

Experimental interest in supraspinal modulation of spinal cord function has a long history. Sherrington [1] first documented that the nociceptive flexion reflex is enhanced following spinal cord transection. Later investigations examined the modulation of flexion reflexes evoked by activation of ‘flexion reflex afferents’ (reviewed in Refs [2,3]); these investigations were, in turn, superseded by interest in the modulation of nociceptive processing in the spinal dorsal horn. The impetus for such studies arose after Reynolds [4] reported that focal electrical http://tins.trends.com

stimulation in the midbrain periaqueductal gray (PAG) of the awake rat produced profound analgesia, a finding reproduced in humans [5,6]. Subsequently, stimulation in discrete regions of the brain has been shown to produce robust antinociception in many species (reviewed in Refs [6,7]). It is not surprising that sites of stimulation-produced analgesia coincide with sites at which microinjection of morphine produces antinociception [8]. Compelling anatomical, electrophysiological and pharmacological evidence has established the rostroventromedial medulla (RVM), stimulation of which can inhibit and/or facilitate nociceptive and non-nociceptive input (Fig. 1), as an integral relay in descending modulation of nociception, including that elicited by PAG stimulation [9–14]. Although the principal focus of investigation has been on the inhibitory modulation of spinal nociceptive processes [7], it has been appreciated for some time that brainstem stimulation can also enhance spinal nociceptive processes. These observations, however, were not systematically investigated until relatively recently. As briefly summarized here, parametric study of modulation of

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Control

(b)

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Fig. 1. Effect of rostroventromedial medulla (RVM) stimulation on responses of a spinal neuron to non-noxious spinal input, produced by back and forth excursion of a soft camel-hair brush across the neuron’s receptive field (shaded). Oscillographic records and corresponding peri-stimulus histograms are shown. Arrows beneath the records indicate back and forth excursion of the brush. (a) Control. (b) Stimulation (duration indicated by horizontal line, onset and termination indicated by arrows) at 50 µA in RVM increased the response to 130% of control. M. Zhuo and G.F. Gebhart, unpublished.

spinal nociceptive reflexes and neurons documented distinct facilitatory and inhibitory influences descending from the brainstem. Accordingly, it was suggested that the descending facilitatory influences could contribute to chronic pain states [15], and subsequently that such influences were important to the development and maintenance of hyperalgesia [16]. Further, facilitation of pain could represent an immune-mediated ‘sickness response’ to infection and inflammation (reviewed in Refs [17–20]). These findings, and others described in this review, support the concept that some chronic pains are sustained by facilitatory influences. Descending facilitation of spinal nociceptive input

Frank Porreca* Michael H. Ossipov Dept of Pharmacology, College of Medicine, University of Arizona Health Sciences Center, Tucson, AZ 85724, USA. *e-mail: frankp@ u.arizona.edu G.F. Gebhart Dept of Pharmacology, The University of Iowa, Iowa City, IA 52242, USA.

Perhaps because it is difficult to envisage the physiological advantages of a pronociceptive system, acceptance of the existence and potential importance of descending facilitatory influences has been slow to develop. Electrical and/or chemical stimulation of sites outside the RVM (e.g. of dorsal reticular [21] or pretectal [22] nuclei) can also enhance behavioral and spinal neuronal responses to peripheral noxious stimulation. However, the RVM has been studied most extensively and is likely to constitute a final common output for rostral brain sites [16,23–30]. Early investigations showed that stimulation in the RVM at relatively high current intensities (50–100 µA) was both antinociceptive (in the tail-flick http://tins.trends.com

test) and responsible for decreased responses of dorsal horn neurons. By contrast, lower current intensities (5–25 µA) at the same sites were facilitatory [23,24,31]. The same studies also characterized sites in the RVM at which only inhibition or only facilitation was produced. Importantly, excitatory neurotransmitters (e.g. glutamate, neurotensin) microinjected into the RVM replicated the effects of stimulation, facilitating and inhibiting spinal nociception at lower and higher doses, respectively, in both electrophysiological and behavioral studies [23,24,32,33] (Fig. 2). Furthermore, microinjection of NMDA into the RVM facilitated the tail-flick reflex in a dose-dependent manner, an effect blocked by the NMDA receptor antagonist APV [26]. One downstream mediator of NMDA-receptor activation, NO, also facilitated the nociceptive reflex, and this effect was blocked by NO synthase inhibition [25]. Activation of these RVM systems results, we believe, from persistent noxious inputs that can enhance pain – that is, pain begets pain. In support of this idea, formalin injected into the tail increased responses of L4–L6 neurons to heating of the hind paw [34]. Similarly, when injected into a hind paw, formalin facilitated reflexes of tail withdrawal from thermal and mechanical noxious stimuli [35]. This effect was abolished by injection of QX-314 – a hydrophilic derivative of the local anesthetic lidocaine – at the site of formalin injection, indicating the need for persistent afferent input to initiate sensitization. A role for the RVM in pain facilitation has also been suggested by studies in which attenuation of RVM activity by microinjection of lidocaine or an electrolytic lesion blocked enhanced nociception [16,27] (Fig. 3). Although the RVM is an important, and perhaps the final, relay in the descending projection of facilitatory influences, it is not necessarily the origin of this mechanism. Midcollicular decerebration has shown the need for a forebrain loop, as this procedure prevented the facilitatory effects of vagal stimulation (which was also blocked by soma-selective lesions in the brainstem) [36]. Stimulation in the RVM produces results that are qualitatively identical to those following vagal afferent stimulation (low intensity stimulation in the RVM facilitates spinal nociceptive reflexes and neuronal responses to noxious input, and is associated with a longer latency to effect than is inhibition of the same reflexes and neurons from the RVM). Few studies have examined facilitation from sites rostral to the RVM, but recently chemical or electrical stimulation in the rat anterior cingulate cortex (ACC), which sends projections to the PAG and thus communicates indirectly with the RVM, enhanced the tail-flick reflex [30]. Intra-RVM microinjection of lidocaine or an antagonist of AMPA and kainate receptors blocked the facilitation produced by electrical stimulation of the ACC [30]. Collectively, these studies suggest that the RVM is a crucial relay in the persistence of descending

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0.03 pmol 30 pmol 300 pmol 3000 pmol

120 100 80 3 min post-NT

60 40 20 0 0 Heat

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30

45 60 Time (min)

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Fig. 2. Effect of chemical rostroventromedial medulla (RVM) stimulation upon noxious inputs to the spinal cord. Low doses of neurotensin (NT) given into RVM enhanced spinal responses to noxious heating of the skin (a) and noxious balloon distension of the colon (b). Greater doses of NT produced dose-dependent inhibition of the same responses (b). Adapted, with permission, from Refs [32,33].

facilitation of noxious inputs. This concept that pain contributes to facilitate pain contrasts with that of diffuse noxious inhibitory controls, in which pain might produce analgesia (reviewed in Refs [37,38]). RVM cells and descending facilitation

Much of what we currently understand about the RVM in relation to processing and modulation of pain is based on the characterizations by Fields and colleagues of three types of neurons found in the RVM. Based on response characteristics to noxious thermal stimulation of the tail, these cells have been described as ‘ON’, ‘OFF’ and ‘neutral’ [15,39,40]. OFF-cells are tonically active and pause in firing immediately before tail (or hind limb) withdrawal from a noxious thermal stimulus. ON-cells accelerate firing immediately before the nociceptive reflex occurs. Neutral cells were initially characterized by the absence of a response to noxious thermal stimulation of the tail; however, these cells respond to noxious stimuli applied elsewhere, and could represent a subtype of ON- or OFF-cells [41]. It was subsequently determined that activation of OFF-cells correlated with inhibition of nociceptive input and nocifensive responses [7,39,40,42]. Because ON-cells increase firing just before a nociceptive reflex, it is unlikely that they are responsible for inhibition of nociception. Rather, the response characteristics of ON-cells are consistent with a role in descending facilitation. ON-cells project from the RVM to the spinal dorsal horn and are likely to also interact with other neurons in the RVM [28,39,40,42,43]. Fields and colleagues [44,45] found that, as a group, ON-cells and OFF-cells fire in a reciprocating pattern, and that tail-flick latency was longer during periods of increased OFF-cell activity and shorter when ON-cells were active. These studies led to the proposal that OFF-cells inhibit, and ON-cells facilitate, transmission of spinal nociceptive input and the subsequent responses [44]. In keeping with http://tins.trends.com

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this idea, manipulations that increase nociceptive responsiveness, thus indicating facilitation, also increase ON-cell activity. Naloxone-precipitated opioid withdrawal is associated with hyperalgesia and also with increased activity of RVM ON-cells [46,47]; this hyperalgesia is abolished by intra-RVM injection of lidocaine, suggesting inhibition of RVM neuronal activity [27,29]. These experimental outcomes suggest that supraspinal sites can contribute to either development or maintenance of chronic pain states, some of which might exist in the absence of obvious pathology. Subsequent studies have broadened this hypothesis; data now support the postulate that a spino–bulbo–spinal loop could be important to the development and maintenance of exaggerated pain behaviors produced by noxious (i.e. hyperalgesic) and non-noxious (i.e. allodynic) peripheral stimuli [16]. The extensive role of ON- and OFF-cells in physiological processes in addition to the modulation of pain has been reviewed recently [48]. Supraspinal modulation of chronic pain

Anatomical and pharmacological criteria suggest that facilitatory and inhibitory pathways are distinct, and are likely to be activated simultaneously in conditions of acute nociception. Thus, a ‘balance’ between these systems could be struck. However, in conditions of persistent nociceptive input, neuroplastic changes might occur in the RVM and elsewhere to yield a sustained facilitatory influence that drives exaggerated pain. Strong evidence supports the idea that manifestations of chronic pain require active participation of supraspinal sites (Table 1). The heightened responses to mechanical or cold, but not to noxious thermal, stimulation, in rats with peripheral nerve injury or hind paw inflammation was abolished by transection of the thoracic spinal cord [49–53]. Selective disruption of the dorsolateral funiculus (DLF) ipsilateral, but not contralateral, to spinal nerve ligation (SNL) abolished tactile and thermal hypersensitivity; DLF transection in sham-operated SNL rats did not affect response thresholds [54]. These results are consistent with the hypothesis that behavioral manifestations of chronic pain states depend on descending facilitation of spinal nociceptive input from the RVM because it is the principal source of descending DLF projections [7,43,55]. The function of the DLF as a conduit of descending inhibition has been well established [7,9]. Ablation of the DLF abolishes the antinociceptive effects of electrical stimulation or morphine applied to the PAG or RVM [43,55]. Because cells in the RVM can both inhibit and facilitate, it is not unexpected that the DLF should also convey descending facilitatory influences from the RVM. It has long been known that electrical stimulation in the DLF can excite dorsal horn neurons in lamina I [56,57]. Spinal cord block confirmed that at least part of this excitation was due to activation of descending fibers, rather than antidromic activation of ascending fibers [57]. These results are in contrast

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(a) Inflammatory pain

(b) Neuropathic pain Lidocaine NT antagonist

Lidocaine CCK antagonist Dermorphin–saporin STT

RVM

RVM RVM EAA,NO, CCK,NT

CCK,MOR ML?

+ Spinal transection Spinal hemisection VLF lesion

+ DLF

VLF

NG

DLF lesion

Injury

DC lesion Aβ fiber

1o hyperalgesia

2o hyperalgesia

Tactile hypersensitivity

Injury

C fiber Thermal hyperalgesia

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Fig. 3. Supraspinal contributions to the maintenance of hyperalgesic inflammatory (a) and neuropathic (b) pain states. (a) Inflammatory pain. Increased nociceptive stimuli arising from tissue injury or inflammation elicit increased afferent input to the spinal dorsal horn, promoting enhanced activity of second-order neurons projecting in the spinothalamic tract (STT) and other ascending tracts with projections to the rostroventromedial medulla (RVM). Sustained nociceptive input enhances activity of cells mediating descending facilitation via the ventrolateral funiculus (VLF). This tonic descending facilitation enhanced further nociceptive inputs, thus increasing pain from the primary injury and also enhancing sensory inputs from adjacent regions (secondary hyperalgesia). Substances that might drive descending facilitation in the RVM include neurotensin (NT), cholecystokinin (CCK), excitatory amino acids (EAAs) and nitric oxide (NO). Manipulations that block enhanced pain include RVM microinjections of lidocaine or NT antagonists, spinal cord transection or hemisection, and lesions of the VLF. (b) Neuropathic pain. Enhanced neuronal activity, driven by ectopic discharge of injured or adjacent fibers following injury to peripheral nerves results in increased input to spinal dorsal horn (via Aβ fibers) and to the nucleus gracilis (NG) via the ascending dorsal column (DC). Such inputs to the NG are likely to be transmitted to other supraspinal sites, possibly to the thalamus via the medial lemniscus (ML). Inputs to supraspinal sites are likely to result ultimately in enhanced descending facilitation from the RVM. Such descending facilitation could be driven by CCK in the RVM and mediated by descending facilitatory cells that express mu-opioid receptors (MOR). Descending facilitation further enhances nociceptive inputs and manifests behaviorally as enhanced pain. Injections of lidocaine, CCK antagonists or dermorphin–saporin conjugate into the RVM to lesion MOR expressing cells, or lesions of the ipsilateral dorsolateral funiculus (DLF), block manifestations of enhanced pain. Similarly, lesions of the DC block manifestations of neuropathic pain.

to reports that RVM-produced facilitation is conveyed principally through spinal ventrolateral funiculi (VLF). RVM-produced facilitation of nociceptive reflexes and responses of spinal neurons to noxious stimulation are blocked by interruption of the VLF, but not by that of the DLF [23,58]. DLF transections, conversely, block the inhibition of spinal nociception by RVM electrical or chemical (e.g. glutamate, neurotensin) stimulation [23,24,32]. Often, previously http://tins.trends.com

inhibitory stimulation in the RVM becomes facilitatory after DLF transection, suggesting that inhibitory influences are dominant and normally mask facilitation [23,24]. Although these experimental outcomes might appear contradictory, the funicular organization of descending inhibitory and facilitatory systems has yet to be studied anatomically. Given the results summarized here, it would appear that both descending inhibitory and facilitatory influences course in both dorsal and ventral parts of the spinal cord. Our interpretation is that persistent activation of supraspinal sites by noxious input, which can be thought of as an additional component of ‘central sensitization’, drives increased spinal sensitivity. Facilitation of painful inputs and neuropathic pain

Converging evidence suggests that some abnormal pain states depend on descending facilitatory drive from the RVM. Persistent noxious input produced by injection of formalin into the hind paw or application of mustard oil to the hind-limb skin facilitates the nocifensive tail-flick reflex [59–61]. Such facilitation of acute pain appears to be mediated through the RVM [59,60], specifically by activation of an NMDA-receptor-mediated mechanism [61,62]. The behavioral signs of neuropathic pain can also be attributed to facilitation of spinal nociceptive input and they are, accordingly, blocked by intra-RVM lidocaine [26,63,64]. Cholecystokinin (CCK), an anti-analgesic peptide, might contribute to RVM neuron excitability. In naïve rats, intra-RVM CCK produces reversible thermal and tactile hypersensitivity [64] and prevents both the activation of OFF-cells and the antinociception produced by systemic morphine [65]. Conversely, intra-RVM

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Table 1. Supraspinal modulation of facilitation of nociceptiona Model of hyperalgesia

Nociceptive response

Manipulation

Effect

Refs

Tactile hypersensitivity in paw

Spinal transection; RVM injected with lidocaine

Block

[27,59]

Paw, outside receptive field

Increased activity of widedynamic-range neurons of the dorsal horn

Spinal transection; RVM injected with lidocaine

Block

[73]

Leg

Facilitation of tail-flick

Spinal transection; electrolytic and chemical lesion of RVM

Block

[25,60]

Enhanced C-fiber mediated ‘wind-up’

Spinal transection

Block

[72]

Thermal hypersensitivity of hind paw

Spinal transection Chemical lesion of RVM

Block No effect

[25] [25]

Facilitation of tail-flick

Electrolytic lesion of RVM

Block

[61,62]

Tactile and thermal hypersensitivity of hind paw

RVM injected with lidocaine Spinal transection RVM injected with dermorphin–saporin DLF lesion Spinal hemisection

Block Block Block

[63,64] [49,51] [68]

Block Block

[54] [49]

Neurogenic inflammation and inflammatory pain Mustard oil Ankle

Carrageenan Knee joint Plantar paw Formalin Paw Neuropathic pain Spinal nerve ligation

Spinal nerve cut

Tactile hypersensitivity of hind paw

Spinal transection

Block

[53]

LPS-induced ‘illness’ Chronic morphine

Facilitation of tail-flick Tactile and thermal hypersensitivity

Electrolytic lesion of RVM RVM lidocaine; bilateral DLF lesion

Block Block

[17,62] [76]

aAbbreviations:

DLF, dorsolateral funiculus; LPS, lipopolysaccharide; RVM, rostroventromedial medulla.

microinjection of a CCK antagonist blocks thermal and tactile hypersensitivity in rats with SNL injury [64]. Direct measurement of changes in the activities of ON- and OFF-cells in correlation with the development of signs of neuropathic pain are prevented by technical difficulties arising from the prolonged development (usually over the course of two to three days) of such pain [66]. An alternative approach to extrapolate the relevance of ON-cell activity to neuropathic pain is to selectively destroy these cells in the RVM. Conjugation of the cytotoxin saporin to a G-protein-coupled-receptor agonist leads to internalization of the ligand–saporin complex and selective destruction of the targeted neuron [67]. Recently, saporin conjugated to the mu-opioidreceptor agonist dermorphin was used to destroy RVM cells expressing the mu-opioid receptor: presumably these included facilitatory ON-cells [68], which are known to express mu-opioid receptors [69]. Rats treated with dermorphin–saporin conjugate, either before or after SNL injury, did not display neuropathic pain behaviors, although normal nociceptive responses were intact. The presumed loss of the ON-cells was suggested to eliminate the descending facilitation required for nerve-injuryinduced pain, by removal of the driving force that maintains tactile and thermal hypersensitivity [68]. http://tins.trends.com

Sustained afferent input after nerve injury is likely to be required at least for initiation of the facilitated pain state, because application of lidocaine to the site of nerve injury abolishes both tactile and thermal hypersensitivity with a time-course consistent with that of lidocaine [66]. Furthermore, SNL diminished the antinociceptive activity of spinal morphine, possibly reflecting an increase in the dose required to compensate for facilitation of nociception [70]. This argument is supported by the fact that the antinociceptive action of spinal morphine was restored by local anesthetic administered close to the site of injury [71]. Additionally, lidocaine applied at the nerve injury site restored the diminished antinociceptive effect of PAG morphine in SNL rats [64]. Thus, it is possible that persistent afferent input, in a manner analogous to repetitive C-fiber activation [33], could promote the development of the facilitated state in the RVM by ultimately increasing ON-cell activity. In support of this argument, attenuation of large-fiber afferent input, either through the microinjection of lidocaine into the nucleus gracilis or by disruption of the dorsal columns, blocked tactile hypersensitivity in rats with SNL without affecting normal nociceptive responses [49]. Importantly, only manipulations made ipsilateral, and not those made contralateral, to the nerve injury attenuated the behavioral manifestations

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of neuropathic pain, confirming the likelihood that the injured nerve, or adjacent uninjured nerves, were the source of the persistent afferent input. Thus, persistent afferent input arising from peripheral nerve injury is likely to produce neuroplastic changes in the RVM. The ultimate consequence of these changes could be facilitation of further nociceptive input that perpetuates the dysesthesias associated with chronic pain states. Facilitation of painful inputs and inflammatory pain

Acknowledgement We thank Herbert Proudfit for assistance with Fig. 3.

Similar experimental strategies to those already described for neuropathic pain effectively block the hyperalgesia that follows peripheral inflammation. Spinal transection or injections of lidocaine into the RVM reverse behavioral and electrophysiological signs of facilitated nociception in rats with carrageenan-induced inflammation of the hind paw [52,72,73]. Complete Freund’s adjuvant (CFA) produces behavioral hyperalgesia and increases expression of Fos-like immunoreactivity (Fos-LI), taken as an indicator of neuronal excitability, in the spinal cords of rats [74]. Intra-RVM pretreatment with the excitotoxic neurotoxin, ibotenic acid, attenuates both the hyperalgesia and Fos-LI expression [74]. Likewise, bilateral lesions of the RVM made with ibotenic acid blocked behavioral signs of secondary hyperalgesia in rats with either intraarticular injection of carrageenan and/or kaolin into the knee, or topical application of mustard oil to the hind leg [24,60]. Experiments involving chemical lesions of RVM somata and physical disruption of descending fibers have further demonstrated that hyperalgesia secondary to inflammation is mediated through descending facilitation from the RVM [24,58].

References 1 Sherrington, C.S. (1906) The Integrative Action of the Nervous System, Yale University Press 2 Lundberg, A. (1967) The supraspinal control of transmission in spinal reflex pathways. Electroencephalogr. Clin. Neurophysiol. (Suppl. 25), 35–46 3 Lundberg, A. (1979) Multisensory control of spinal reflex pathways. Prog. Brain Res. 50, 11–28 4 Reynolds, D.V. (1969) Surgery in the rat during electrical analgesia induced by focal brain stimulation. Science 164, 444–445 5 Young, R.F. and Brechner, T. (1986) Electrical stimulation of the brain for relief of intractable pain due to cancer. Cancer 57, 1266–1272 6 Mayer, D.J. (1984) Analgesia produced by electrical stimulation of the brain. Prog. Neuropsychopharmacol. Biol. Psychiatry 8, 557–564 7 Fields, H.L. and Basbaum, A.I. (1999) Central nervous system mechanisms of pain modulation. In Textbook of Pain (Wall, P.D. and Melzack, R., eds), pp. 309–329, Churchill Livingstone 8 Yeung, J.C. et al. (1977) Concurrent mapping of brain sites for sensitivity to the direct application of morphine and focal electrical stimulation in the production of antinociception in the rat. Pain 4, 23–40 http://tins.trends.com

Finally, time-dependent increases in RVM activity associated with facilitation and inhibition were observed following persistent hind-paw inflammation, indicating a dynamic plasticity of the RVM in response to persistent pain [75]. It was suggested that enhanced facilitation could reflect an upregulation of NMDA receptors in the RVM, induced by persistent nociceptive inputs [75]. These studies provide evidence that prolonged noxious stimulation might activate descending facilitatory influences from the RVM, which in turn lead to enhanced pain-related behaviors. Concluding remarks

Our understanding of nociceptive circuits, especially those that actually promote pain, is still in its infancy. Pain has important physiological functions, warning us of actual or impending tissue damage. Less obvious is the physiological importance of mechanisms for pain facilitation. In the case of persistent injury, it is easy to postulate that these mechanisms exist to protect the injured region by forcing guarding behavior and restricting the use of the injured site. Neuropathic pain, however, persists long after the initial injury has healed, does not serve a protective mechanism and is more difficult to understand. Perhaps nerve injury engages a nocifensive system that is normally activated for defensive purposes, but which can become a source of prolonged and exaggerated abnormal pain. With this in mind, we suggest that the identification of mediators of facilitatory activity in, or from, the RVM might lead to the development of novel therapeutic approaches for the treatment of abnormal chronic pain states.

9 Fields, H.L. and Basbaum, A.I. (1978) Brainstem control of spinal pain-transmission neurons. Annu. Rev. Physiol. 40, 217–248 10 Fields, H.L. et al. (1977) Nucleus raphe magnus inhibition of spinal cord dorsal horn neurons. Brain Res. 126, 441–453 11 Fields, H.L. et al. (1976) Nucleus raphe magnus: a common mediator of opiate- and stimulusproduced analgesia. Trans. Am. Neurol. Assoc. 101, 208–210 12 Behbehani, M.M. and Fields, H.L. (1979) Evidence that an excitatory connection between the periaqueductal gray and nucleus raphe magnus mediates stimulation produced analgesia. Brain Res. 170, 85–93 13 Sandkuhler, J. and Gebhart, G.F. (1984) Relative contributions of the nucleus raphe magnus and adjacent medullary reticular formation to the inhibition by stimulation in the periaqueductal gray of a spinal nociceptive reflex in the pentobarbitalanesthetized rat. Brain Res. 305, 77–87 14 Gebhart, G.F. et al. (1983) Inhibition of spinal nociceptive information by stimulation in midbrain of the cat is blocked by lidocaine microinjected in nucleus raphe magnus and medullary reticular formation. J. Neurophysiol. 50, 1446–1459 15 Fields, H.L. (1992) Is there a facilitating component to central pain modulation? Am. Pain Soc. J. 1, 71–78

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