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Supraspinal Contributions to Hyperalgesia

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Supraspinal Contributions to Hyperalgesia Proc. Natl. Acad. Sci. USA Vol. 96, pp. 7687–7692, July 1999 Colloquium Paper This paper was presented at the National Academy of Sciences colloquium ‘‘The Neurobiology of Pain,’’ held December 11–13, 1998, at the Arnold and Mabel Beckman Center in Irvine, CA. Supraspinal contributions to hyperalgesia M. O. URBAN AND G. F. GEBHART* Department of Pharmacology, College of Medicine, University of Iowa, Iowa City, IA 52242 ABSTRACT Tissue injury is associated with sensitization eral tissue damage did not require ongoing peripheral input, of nociceptors and subsequent changes in the excitability of and that spinal dorsal horn neuron receptive fields expanded, central (spinal) neurons, termed central sensitization. Noci- responsiveness to suprathreshold stimuli increased, response ceptor sensitization and central sensitization are considered thresholds decreased, and sensitivity to novel stimuli was to underlie, respectively, development of primary hyperalgesia acquired after peripheral injury. The focus of investigation has and secondary hyperalgesia. Because central sensitization is remained the spinal cord, and many investigators have since considered to reflect plasticity at spinal synapses, the spinal documented the importance of the spinal N-methyl-D- cord has been the principal focus of studies of mechanisms of aspartate (NMDA) receptor to the induction and maintenance hyperalgesia. Not surprisingly, glutamate, acting at a spinal of central sensitization (see ref. 6 for recent overview). A N-methyl-D-aspartate (NMDA) receptor, has been implicated growing body of evidence, however, reveals a significant in development of secondary hyperalgesia associated with contribution of descending influences from supraspinal sites in somatic, neural, and visceral structures. Downstream of the development and maintenance of central sensitization͞ NMDA receptor activation, spinal nitric oxide (NO⅐), protein secondary hyperalgesia. We review here and discuss evidence kinase C, and other mediators have been implicated in main- that peripheral tissue injury engages spinobulbospinal circuitry taining such hyperalgesia. Accumulating evidence, however, that may be important to the development and maintenance of reveals a significant contribution of supraspinal influences to central sensitization and secondary hyperalgesia. development and maintenance of hyperalgesia. Spinal cord Descending Facilitation. Although the potency of descend- transection prevents development of secondary, but not pri- ing inhibitory influences has long been appreciated, the study mary, mechanical and͞or thermal hyperalgesia after topical and characterization of descending facilitatory influences have mustard oil application, carrageenan inflammation, or nerve- been more recent developments. Interestingly, inhibitory and root ligation. Similarly, inactivation of the rostral ventrome- facilitatory influences can be produced at many of the same dial medulla (RVM) attenuates hyperalgesia and central sites in the brainstem, particularly in the rostral ventromedial sensitization in several models of persistent pain. Inhibition of medulla (RVM). Generally, low intensities of electrical stim- medullary NMDA receptors or NO⅐ generation attenuates ulation or low concentrations of chemical (e.g., glutamate, somatic and visceral hyperalgesia. In support, topical mustard neurotensin) facilitate spinal nociception, whereas greater oil application or colonic inflammation increases expression intensities of stimulation or concentrations of chemical at the of NO⅐ synthase in the RVM. These data suggest a prominent same sites typically inhibit spinal nociception (7–10). These role for the RVM in mediating the sensitization of spinal dual influences appear to involve anatomically distinct inde- neurons and development of secondary hyperalgesia. Results pendent spinal pathways and are mediated by different lumbar to date suggest that peripheral injury and persistent input spinal receptors. For example, high-intensity electrical stimu- engage spinobulbospinal mechanisms that may be the prepo- lation or high-dose glutamate or neurotensin injection into the tent contributors to central sensitization and development of RVM inhibits spinal nociceptive transmission via descending secondary hyperalgesia. projections in the dorsolateral funiculi and activation of spinal cholinergic and monoaminergic receptors. In contrast, facili- Hardy et al. (1) investigated two types of experimentally tatory influences from the RVM produced by electrical stim- produced cutaneous hyperalgesia, primary and secondary. ulation, glutamate injection, or neurotensin injection involve Primary hyperalgesia occurs at the site of injury; secondary descending projections in the ventrolateral funiculi and are hyperalgesia is associated with the injury, but occurs in ‘‘un- mediated by spinal serotonin and cholecystokinin receptors. damaged tissues adjacent to and at some distance from the site (7, 9, 11–13). of an injury.’’ They proposed a ‘‘new formulation’’ to explain In addition to the RVM, adjacent medullary sites also have the spread of hyperalgesia away from the site of injury, namely been implicated in descending facilitation of spinal nociceptive that a central (spinal) excitatory state, and not a peripheral transmission. Electrical and͞or selective chemical stimulation mechanism as advanced by Lewis (2), was responsible for in these areas have been shown to enhance spinal behavioral secondary hyperalgesia. Subsequent intensive study of the and dorsal horn neuron responses to noxious stimulation (14). altered sensations that arise from and adjacent to injured Fields et al. (15) have characterized cells in the RVM that tissues has supported this ‘‘formulation’’ and it is now widely may constitute the physiological basis for generation of bidi- accepted that mechanisms of primary and secondary hyper- rectional modulation of spinal nociceptive transmission. They algesia are, respectively, peripheral and central (e.g., see refs. have operationally defined three classes of neurons in the 3, 4). RVM: on-cells, off-cells, and neutral cells, which are inter- The increase in excitability of spinal neurons after periph- mixed in the RVM and not anatomically separable. Off-cells eral injury, termed central sensitization, has been extensively studied by Woolf and colleagues (see ref. 5 for overview). They Abbreviations: NMDA, N-methyl-D-aspartate; RVM, rostral ventro- documented that the enhanced reflex excitability after periph- medial medulla; NO⅐, nitric oxide; LPS, lipopolysaccharide; NTS, nucleus tractus solitarius; APV, 2-amino-5-phosphonovaleric acid. *To whom reprint requests should be addressed. e-mail: gf- PNAS is available online at www.pnas.org. [email protected]. 7687 Downloaded by guest on September 26, 2021 7688 Colloquium Paper: Urban and Gebhart Proc. Natl. Acad. Sci. USA 96 (1999) display an abrupt pause in ongoing activity immediately before concluded that persistent nociceptor stimulation by topical nociceptive reflexes and are proposed to contribute to inhib- mustard oil activates a positive feedback loop involving de- itory influences that descend from the RVM. On-cells display scending facilitatory influences from the RVM. In an electro- a burst of activity immediately before nociceptive reflexes and physiological study of spinal cord neurons, Pertovaara (27) are proposed to contribute to facilitatory influences that subsequently reported that midthoracic spinal transection or descend from the RVM. Neutral cells show no nociception- lidocaine inactivation of the RVM blocked mustard oil- related change in activity. Off-cells, on-cells, and neutral cells induced enhanced excitability of wide dynamic range neurons all project to the spinal dorsal horn (16), placing on-cell and to mechanical stimulation. In these experiments, mustard oil off-cell terminals in appropriate laminae (I, II, and V) to was applied 1–2 cm outside the border of the receptive field of modulate nociceptive transmission. That on- and off-cells the spinal neuron. Thus, in both studies, the allodynia͞ mediate descending facilitatory and inhibitory influences from hyperalgesia was tested at a site distant from the site of the RVM is supported by several reports demonstrating en- application of mustard oil (i.e., it was secondary in nature). hanced on- or off-cell activity during facilitation or inhibition In related studies, we documented a significant contribution of spinal nociceptive transmission, respectively (17–19). of descending facilitatory influences in a model of thermal We hypothesize that there exists a spinobulbospinal circuit hyperalgesia involving topical application of mustard oil to the that contributes significantly to central sensitization and sec- hind leg and measurement of the spinal nociceptive tail-flick ondary hyperalgesia. Anatomically, this circuit is in place. Both reflex (28). It was found that midthoracic spinal transection or the RVM and adjacent areas receive direct afferent input from electrolytic lesion of the RVM prevented facilitation of the the superficial spinal dorsal horn and in turn send descending tail-flick reflex produced by mustard oil. To confirm an projections through spinal funiculi that terminate in the su- involvement of cells in the RVM in modulating this secondary perficial dorsal horn, completing a spinobulbospinal loop thermal hyperalgesia, we found that RVM lesion using the (20–23). We review below recent studies that document that soma-selective neurotoxin ibotenic acid resulted
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