Cover Image

Not for Sale



View/Hide Left Panel
Click for next page ( 7688


The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 7687
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 hyperalgesia. Not surprisingly, glutamate, acting at a spinal N-methyl-D-aspartate (NMDA) receptor, has been implicated in development of secondary hyperalgesia associated with somatic, neural, and visceral structures. Downstream of NMDA receptor activation, spinal nitric oxide (NO ), protein kinase C, and other mediators have been implicated in main taining such hyperalgesia. Accumulating evidence, however, reveals a significant contribution of supraspinal influences to development and maintenance of hyperalgesia. Spinal cord transection prevents development of secondary, but not pri mary, mechanical and/or thermal hyperalgesia after topical mustard oil application, carrageenan inflammation, or nerve root ligation. Similarly, inactivation of the rostral ventrome dial medulla (RVM) attenuates hyperalgesia and central sensitization in several models of persistent pain. Inhibition of medullary NMDA receptors or NO generation attenuates somatic and visceral hyperalgesia. In support, topical mustard oil application or colonic inflammation increases expression of NO synthase in the RVM. These data suggest a prominent role for the RVM in mediating the sensitization of spinal neurons and development of secondary hyperalgesia. Results to date suggest that peripheral injury and persistent input engage spinobulbospinal mechanisms that may be the prepo tent contributors to central sensitization and development of secondary hyperalgesia. ~. Hardy et al. (1) investigated two types of experimentally produced cutaneous hyperalgesia, primary and secondary. Primary hyperalgesia occurs at the site of injury; secondary hyperalgesia is associated with the injury, but occurs in "un- damaged tissues adjacent to and at some distance from the site of an injury." They proposed a "new formulation" to explain the spread of hyperalgesia away from the site of injury, namely that a central (spinal) excitatory state, and not a peripheral mechanism as advanced by Lewis (2), was responsible for secondary hyperalgesia. Subsequent intensive study of the altered sensations that arise from and adjacent to injured tissues has supported this "formulation" and it is now widely accepted that mechanisms of primary and secondary hyper- algesia are, respectively, peripheral and central (e.g., see refs. 3, 4~. The increase in excitability of spinal neurons after periph- eral injury, termed central sensitization, has been extensively studied by Woolf and colleagues (see ref. 5 for overview). They documented that the enhanced reflex excitability after periph PNAS is available online at www.pnas.org. aspartate (NMDA) receptor to the induction and maintenance of central sensitization (see ref. 6 for recent overview). A growing body of evidence, however, reveals a significant contribution of descending influences from supraspinal sites in the development and maintenance of central sensitization/ secondary hyperalgesia. We review here and discuss evidence that peripheral tissue injury engages spinobulbospinal circuitry that may be important to the development and maintenance of central sensitization and secondary hyperalgesia. Descending Facilitation. Although the potency of descend- ing inhibitory influences has long been appreciated, the study and characterization of descending facilitatory influences have been more recent developments. Interestingly, inhibitory and facilitatory influences can be produced at many of the same sites in the brainstem, particularly in the rostral ventromedial medulla (RVM). Generally, low intensities of electrical stim- ulation or low concentrations of chemical (e.g., glutamate, neurotensin) facilitate spinal nociception, whereas greater intensities of stimulation or concentrations of chemical at the same sites typically inhibit spinal nociception (7-10~. These dual influences appear to involve anatomically distinct inde- pendent spinal pathways and are mediated by different lumbar spinal receptors. For example, high-intensity electrical stimu- lation or high-dose glutamate or neurotensin injection into the RVM inhibits spinal nociceptive transmission via descending projections in the dorsolateral funiculi and activation of spinal cholinergic and monoaminergic receptors. In contrast, facili- tatory influences from the RVM produced by electrical stim- ulation, glutamate injection, or neurotensin injection involve descending projections in the ventrolateral funiculi and are mediated by spinal serotonin and cholecystokinin receptors. (7, 9, 11-13~. In addition to the RVM, adjacent medullary sites also have been implicated in descending facilitation of spinal nociceptive transmission. Electrical and/or selective chemical stimulation in these areas have been shown to enhance spinal behavioral and dorsal horn neuron responses to noxious stimulation (14~. Fields et al. (~15) have characterized cells in the RVM that may constitute the physiological basis for generation of bidi- rectional modulation of spinal nociceptive transmission. They have operationally defined three classes of neurons in the RVM: on-cells, off-cells, and neutral cells, which are inter- mixed in the RVM and not anatomically separable. Off-cells Abbreviations: NMDA, N-methyl-D-aspartate; RVM, rostral ventro- medial medulla; NO, nitric oxide; LPS, lipopolysaccharide; NTS, nucleus tractus solitaries; APV, 2-amino-5-phosphonovaleric acid. *To whom reprint requests should be addressed. e-mail: gf- gebhart@uiowa.edu. 7687

OCR for page 7687
7688 Colloquium Paper: Urban and Gebhart display an abrupt pause in ongoing activity immediately before nociceptive reflexes and are proposed to contribute to inhib- itory influences that descend from the RVM. On-cells display a burst of activity immediately before nociceptive reflexes and are proposed to contribute to facilitatory influences that descend from the RVM. Neutral cells show no nociception- related change in activity. Off-cells, on-cells, and neutral cells all project to the spinal dorsal horn (16), placing on-cell and off-cell terminals in appropriate laminae (I, II, and V) to modulate nociceptive transmission. That on- and off-cells mediate descending facilitatory and inhibitory influences from the RVM is supported by several reports demonstrating en- hanced on- or off-cell activity during facilitation or inhibition of spinal nociceptive transmission, respectively (17-194. We hypothesize that there exists a spinobulbospinal circuit that contributes significantly to central sensitization and sec- ondary hyperalgesia. Anatomically, this circuit is in place. Both the RVM and adjacent areas receive direct afferent input from the superficial spinal dorsal horn and in turn send descending projections through spinal funiculi that terminate in the su- perficial dorsal horn, completing a spinobulbospinal loop (20-23~. We review below recent studies that document that spinal transection, or inactivation of supraspinal sites, prevents the expression of secondary hyperalgesia in a variety of animal models of persistent inflammatory, neurogenic, or neuro- pathic pain, thus providing the functional context in support of the anatomy (see Table 1~. Inflammatory/Neurogenic Models of Hyperalgesia. Mus- tard oil. Mustard oil (allyl isothiocyanate) is a chemical irritant that produces a neurogenic inflammation and excites chemo- sensitive C-fibers, resulting in behavioral hyperalgesia and central sensitization (24, 25~. An involvement of supraspinal sites in mustard oil-induced sensitization was reported by Mansikka and Pertovaara (26), who found that tactile allo- dynia of the glabrous skin of the foot after topical application of mustard oil to the ankle was prevented in animals that had received spinal transection. Additionally, in spinally intact rats, the tactile allodynia was blocked after inactivation of the medial RVM by local lidocaine microinjection. The authors Table 1. Summary of supraspinal contributions to hyperalgesia Proc. Natl. Acad. Sc'. USA 96 (1999J concluded that persistent nociceptor stimulation by topical mustard oil activates a positive feedback loop involving de- scending facilitatory influences from the RVM. In an electro- physiological study of spinal cord neurons, Pertovaara (27) subsequently reported that midthoracic spinal transection or lidocaine inactivation of the RVM blocked mustard oil- induced enhanced excitability of wide dynamic range neurons to mechanical stimulation. In these experiments, mustard oil was applied 1-2 cm outside the border of the receptive field of the spinal neuron. Thus, in both studies, the allodynia/ hyperalgesia was tested at a site distant from the site of application of mustard oil (i.e., it was secondary in nature). In related studies, we documented a significant contribution of descending facilitatory influences in a model of thermal hyperalgesia involving topical application of mustard oil to the hind leg and measurement of the spinal nociceptive tail-flick reflex (28~. It was found that midthoracic spinal transection or electrolytic lesion of the RVM prevented facilitation of the tail-flick reflex produced by mustard oil. To confirm an involvement of cells in the RVM in modulating this secondary thermal hyperalgesia, we found that RVM lesion using the soma-selective neurotoxin ibotenic acid resulted in a similar block of mustard oil-induced hyperalgesia (29~. Active participation of descending facilitatory influences from the RVM in modulating mustard oil-induced hyperalge- sia is supported further by evidence that NMDA and neuro- tensin receptors in the RVM modulate this secondary thermal hyperalgesia. As indicated above, neurotensin receptors (7, 8) and NMDA receptors (30, 31) in the RVM have been impli- cased in descending facilitation of spinal nociception. Selective blockage of these receptors should then modulate hyperalge- sia. Indeed, intra-RVM injection of a selective neurotensin receptor antagonist (SR48692) or NMDA receptor antagonist t2-amino-5-phosphonovaleric acid (APV)] fully and dose de- pendently prevented mustard oil-induced facilitation of the tail-flick reflex (28, 30~. It is known that generation of nitric oxide (NO) is one downstream consequence of NMDA re- ceptor activation (324. In complementary studies, we showed that intra-RVM administration of the NO-synthase inhibitor Model of hyperalgesia Nociceptive response Manipulation Inf lammation/neurogenic Mustard oil (ankle) Mustard oil (foot, outside receptive field) Mustard oil (leg) Carrageenan (knee joint) Carrageenan (knee joint) Carrageenan (planter foot) Formalin (foot) Neuropathic Spinal nerve ligation Spinal nerve ligation Spinal nerve cut Illness LPS (intraperitoneal) Effect Tactile allodynia, foot Enhanced excitability of WDR dorsal horn neurons Facilitation of the thermal tail-flick reflex Enhanced C-fiber-mediated flexor motoneuron wind-up Facilitation of the thermal paw-withdrawal response Facilitation of the thermal paw-withdrawal response Facilitation of the thermal tail-flick reflex Tactile allodynia, foot Tactile allodynia, foot Facilitation of the thermal paw-withdrawal response Tactile allodynia, foot Facilitation of the thermal tail-flick reflex Spinal transection Intra-RVM lidocaine Spinal transection Intra-RVM lidocaine Spinal transection Electrolytic RVM lesion Ibotenic acid RVM lesion Spinal transection Intra-RVM lidocaine Ibotenic acid RVM lesion Intra-RVM lidocaine Ibotenic acid RVM lesion Spinal transection Electrolytic RVM lesion Intra-RVM lidocaine Spinal transection Spinal transection Ref. Block Block 26 27 Block 28, 29 Block 37 Block 29 No effect 29 block 41, 42 Block Block Block Electrolytic RVM lesion Block Electrolytic NTS lesion 44 45 46 42 , 50

OCR for page 7687
Colloquium Paper: Urban and Gebhart N~-nitro-~-arginine methyl ester (~-NAME), like the NMDA receptor antagonist APV, attenuated mustard oil-induced hyperalgesia (30~. Conversely, microinjection of the NO donor GEA 5024 (or of NMDA itself) dose dependently facilitated the tail-flick reflex in naive rats. The involvement of NO in the RVM was further supported by a significant increase in the number of NADPH-diaphorase-labeled cells at the time of maximal mustard oil-induced hyperalgesia. Finally, in a model of visceral hyperalgesia in which the inflammogen zymosan is instilled into the colon, both APV and -NAME given into the RVM 3 hr after colonic inflammation reversed the hyperal- gesia for the duration of drug action, suggesting that the RVM plays a role in maintenance of the hyperalgesia (31~. Similar to what was seen in the model of mustard oil hyperalgesia, both NADPH-diaphorase-labeled cell numbers and the number of cells immunostained for the neuronal isoform of NO -synthase were significantly increased in the RVM 3 hr after colonic inflammation. These results support a role for descending facilitatory influences in the maintenance of mustard oil- induced and visceral hyperalgesia involving activation of NMDA and neurotensin receptors in the RVM. Carrageenan. Several models of hyperalgesia involving sub- cutaneous injection of carrageenan have been characterized. Carrageenan is a water-extractable polysaccharide obtained from various seaweeds. Injection of lambda carrageenan (a hydrocolloid that does not form a gel) into the planter foot, or intraarticular injection into the knee joint, results in a localized inflammation, decreased weight bearing, guarding of the af- fected limb, and hyperalgesia (e.g., refs. 33 and 34~. Carrag- eenan-induced hyperalgesia is believed to occur as a conse- quence of sensitization of primary afferent nociceptors and neuron plasticity intrinsic to the spinal cord (35, 36~. Herrero and Cervero (37) first reported that the A- and C-fiber mediated wind-up of flexor motoneurons after intra- articular (knee) carrageenan injection was prevented by spinal transection. They concluded that supraspinal modulatory sys- tems, either direct excitatory influences on spinal neurons or release of local inhibitory controls, are essential for wind-up. We examined a potential contribution of descending facilita- tory influences from the RVM to enhanced behavioral noci- ceptive responses after intraplantar or intraarticular (knee) injection of carrageenan (29~. Intraplantar injection of carra- geenan and subsequent thermal stimulation of the planter surface of the hindpaw is a model of primary hyperalgesia; intraarticular injection of carrageenan and subsequent thermal stimulation of the planter surface of the hindpaw is a model of secondary hyperalgesia. Inactivation of the RVM by lidocaine microinjection reversed, and prior permanent inactivation of the RVM by ibotenic acid lesion completely blocked, facilita- tion of the thermal paw-withdrawal response after intraartic- ular carrageenan injection. RVM inactivation by either lido- caine or ibotenic acid was ineffective, however, in preventing thermal hyperalgesia after intraplantar carrageenan injection (i.e., model of primary hyperalgesia). These results suggest that these two models of carrageenan-induced thermal hyperalge- sia are differentially modulated in the central nervous system. Additionally, similar to mustard oil-induced secondary hyper- algesia, intra-RVM injection of a selective neurotensin recep- tor antagonist (SR48692) or NMDA receptor antagonist (APV) was found to block facilitation of the thermal paw- withdrawal response after intraarticular, but not intraplantar, carrageenan injection (Fig. 1~. These results further support a contribution of descending facilitatory influences to secondary hyperalgesia that is mediated by neurotensin and NMDA receptors in the RVM. Formalin. Subcutaneous injection of formalin into the dor- sum of the rodent hindpaw is a well characterized model in which animals exhibit spontaneous pain behaviors (shaking, licking of the injected hindpaw) as well as hyperalgesia (38, 39~. Additionally, formalin has been shown to produce secondary Proc. Nail. Acad. Sci. USA 96 (1999J 7689 hyperalgesia after subcutaneous injection into either the hind- paw or tail (40, 41~. A significant contribution of supraspinal sites to formalin-produced secondary hyperalgesia was re- ported by Wiertelak et al. (41), who found that spinal tran- section prevented facilitation of the tail-flick reflex after formalin injection into the hindpaw. That activation of de- scending facilitatory influences from the RVM modulates this hyperalgesia was subsequently supported by the finding that electrolytic lesion of the RVM prevented facilitation of the tail-flick reflex after formalin injection (42~. Neuropathic Models of Hyperalgesia. Animal models of neuropathic pain generally involve loose ligation of peripheral nerves, which results in spontaneous pain behaviors, enhanced responses of spinal-dorsal horn nociceptive neurons, and hy- peralgesia (for review, see ref. 43~. A contribution of supraspi- nal sites to neuropathic pain after spinal nerve ligation was initially reported by Pertovaara et al. (44~. In that study, the tactile allodynia that develops after unilateral ligation of the L5 and L6 spinal nerves was found to be attenuated by inactivation of the RVM by lidocaine injection. The lidocaine effect was determined to be localized within the RVM and independent of an opioid mechanism, suggesting an inactivation of a descending facilitatory influence from the RVM. These results were supported in a subsequent study (45), in which spinal fr~nsec.tion was found to abolish the tactile allodynia as well as thermal hyperalgesia produced by ligation of the Ls and L6 spinal nerves. Additionally, Kauppila (46) found spinal tran- section to block mechanical hyperalgesia observed after a chronic sciatic nerve cut. Thus, neuropathic pain after periph- eral nerve injury appears to involve, at least in part, activation of descending facilitatory influences from supraspinal sites, including the RVM. . ropcapli9 Illness-Induced Models of Hyperalgesia. The systemic ad- ministration of lipopolysaccharide (LPS) has been shown to produce a number of symptoms associated with illness, such as fever, lethargy, decreased food and water intake, and increased sleep (for review, see ref. 47~. Additionally, administration of LPS produces hyperalgesia through the release of peripheral cytokines (e.g., IL-1~3) from immune cells (48, 49~. In a series of experiments, Watkins et al. (49, 50) determined that facil- itation of the tail-flick reflex after intraperitoneal injection of LPS does not involve primary afferent nociceptor input to the spinal dorsal horn. Instead, a novel circuit was proposed involving IL-113 activation of hepatic vagal afferent fibers that terminate in the nucleus tractus solitarius (NTS). Consistent with this proposal, electrolytic lesion of the NTS or RVM was found to block facilitation of the tail-flick reflex produced by intraperitoneal LPS. Because the NTS and RVM are recipro- cally connected, direct afferent input to the RVM may mediate this effect, although Watkins et al. (50) implicated an uniden- tified site rostral to the midmesencephalon as an important relay. This interpretation is consistent with earlier studies of biphasic effects of electrical stimulation of vagal afferent fibers (see ref. 51 for review). In those experiments, low-intensity stimulation of vagal afferent fibers was documented to facil- itate spinal nociceptive reflexes (tail-flick reflex) and spinal dorsal horn neuron responses to noxious stimuli. The facili- tatory effect of vagal stimulation was abolished after midcol- licular decerebration, implicating an NTS-forebrain circuit in descending inf luences that ultimately exit the brainstem via the RVM. Although the tail-flick reflex is a spinally organized response. facilitation of this reflex after intraperitoneal LPS similarly appears to involve activation of descending facilita- tory influences from the RVM. Primary vs. Secondary Hyperalgesia. We and others have studied the effects of spinal cord transection and of reversible (lidocaine) or permanent (ibotenic acid) inactivation of the RVM in models of primary and secondary hyperalgesia after peripheral tissue insult. The results reviewed above uniformly support the hypothesis that facilitatory influences from the

OCR for page 7687
7690 Colloquium Paper: Urban and Gebhart primary hyperalgesia A (carra foot) 20 o/o o -20 -40 -60 B 20 o/o O -20 -40 -60 C20 o/o o -20 -40 -60 secondary hyperalgesia (carra knee) sham ibotenic acid sham ibotenic acid vein. APV vein. APV vein. SR48692 vein. SR48692 FIG. 1. Involvement of descending facilitatory influences from the RVM in models of secondary, but not primary, thermal hyperalgesia after peripheral inflammation. (A) RVM lesion produced by ibotenic acid prevented facilitation of the thermal paw-withdrawal response after intraarticular carrageenan/kaolin injection into the knee (t test, P < 0.05), but was ineffective in preventing facilitation of the thermal paw-withdrawal response after intraplantar carrageenan injection into the foot (model of primary hyperalgesia). (B) Intra-RVM microin- jection of the NMDA receptor antagonist APV (1 pmol/1 Al), or (C) Intra-RVM microinjection of the neurotensin receptor antagonist SR48692 (3 nmol/1 ill) attenuated secondary, but not primary, hyperalgesia (t test, P < 0.05~. All data are represented as mean + SEM of the percent change in thermal paw-withdrawal latency (%) from the control response for the ipsilateral (inflamed) hindlimb. In experiments involving ibotenic acid RVM lesion, responses are rep- resented at the time of maximal hyperalgesia (3 hr after carrageenan injection). Intra-RVM microinjection of APV or SR48692 was per- formed at the time of maximal hyperalgesia (3 fur), and responses are represented at the time of maximal drug effect after Intra-RVM injection (10 min). brainstem significantly contribute to secondary, but not pri- mary, hyperalgesia. What has not yet been addressed specif- ically is whether the RVM is necessary and sufficient for development or for maintenance of secondary hyperalgesia. Intra-RVM injection of lidocaine reverses, in a time-limited Proc. Nail. Acad. Sci. USA 96 (1999' fashion, already established secondary hyperalgesia, suggest- ing a clear role for the RVM in maintenance of secondary hyperalgesia. Other studies reveal that spinal-cord transection or soma-selective lesion of the RVM prevents development of secondary, but not primary, hyperalgesia. Accordingly, avail- able evidence suggests that the RVM is important to both the development and maintenance of secondary hyperalgesia. The studies reviewed here all have examined behavioral conse- quences of peripheral tissue insult, and there are limited data available yet with respect to the direct influence of the RVM on spinal neuron plasticity (central sensitization). Two studies have examined changes in spinal neuron be- havior associated with peripheral tissue insult. Schaible et al. (52) examined, in the cat, the effect of acute inflammation of the knee joint with a mixture of kaolin and carrageenan on spinal dorsal horn neurons. They documented that spontane- ous activity and responses to both innocuous and noxious stimulation of the joint were increased progressively as the inflammation progressed. Neuron activity and responses to stimulation were increased further when spinal cord transmis- sion was interrupted temporarily by cold block of the lower thoracic spinal cord. They concluded that spinal neuron hy- perexcitability associated with a peripheral inflammation was counteracted by enhancement of descending inhibitory influ- ences. Ren and Dubner (53) studied, in the rat, the effect of lidocaine injection into the midline RVM on spinal neuron responses to stimulation of a hindpaw inflamed with complete Freund's adjuvant. During the action of lidocaine, neuron spontaneous activity and responses to mechanical and thermal stimulation applied to the hindpaw were significantly in- creased, which was interpreted to indicate that peripheral inflammation leads to an enhanced descending inhibition. Both of these studies used models of primary hyperalgesia (stimuli were applied to the injured tissue). Both also noted, however, an increase in the size of neuron receptive fields, usually taken as an indication of secondary hyperalgesia. Although neither report directly addresses the hypothesis advanced here, both contribute relevant information. Both document an active modulation by the brainstem of spinal neuron excitability in the presence of tissue injury, confirming activation by peripheral noxious inputs of descending inhibi- tion that can modulate further spinal nociceptive transmission. The generality of the present hypothesis remains to be established. Most of the studies done to date have examined secondary thermal hyperalgesia. Thermal hyperalgesia is widely used in studies with nonhuman animals, but second- ary thermal hyperalgesia is not of significant consequence in most instances of tissue injury in humans. The extent to which secondary mechanical hyperalgesia is modulated by the RVM is unclear. The limited data available to date relate to tactile allodynia and mechanical hyperalgesia in models of neuropathic pain. Additional studies that use other models of hyperalgesia are necessary. Models of chemically pro- duced hyperalgesia, which may involve more selective actions on different types of nociceptors, have not been studied extensively. Secondary thermal hyperalgesia produced by topical application of the C-fiber excit ant mustard oil has been documented by several investigators to be influenced by the RVM. Whether secondary hyperalgesia produced by intradermal injection of capsaicin, which acts at the va- nilloid-1 receptor, is similarly modulated by the RVM has not been reported. It is also unknown how blockage of central sensitization at the level of the spinal cord (by antagonism of the NMDA receptor, for example) influences the RVM. It may be that the spinal cord and RVM are both necessary and sufficient to development and maintenance of secondary hyperalgesia. Results reviewed here clearly indicate that central sensitization at the level of the spinal cord can be modulated by the RVM, even if the spinal cord is the portal of first entry of the relevant

OCR for page 7687
Colloquium Paper: Urban and Gebhart 1 hyperaigesia site of injury / 2 hyperalgesia it/ / +( /~1 1 Act\ ~ / 1:~:~::~ ~ \ \ Proc. Natl. Acad. Sci. USA 96 (1999J 7691 \ ~: ~ / . ~ ~ ~ x~ NO _~ I/ \ ) DOG FIG. 2. Summary diagram illustrating a significant supraspinal contribution to secondary, but not primary, thermal hyperalgesia after peripheral inflammation. Peripheral injury results in activation and sensitization of peripheral nociceptors and subsequent enhanced excitability of dorsal horn nociceptive neurons (central sensitization) that contributes to primary hyperalgesia (at site of injury) and secondary hyperalgesia (adjacent/distant from site of injury). Additionally, it is proposed that stimulation of nociceptors activates a spinobulbospinal loop, engaging a centrifugal descending nociceptive facilitatory influence from the RVM. Facilitatory influences are activated by NMDA receptors and NO, and neurotensin (NT) receptors in the RVM and descend to multiple spinal segments to contribute significantly to secondary hyperalgesia. In contrast, primary hyperalgesia does not involve descending facilitatory influences from supraspinal sites and is likely the direct result of peripheral nociceptor sensitization and neuroplasticity intrinsic to the spinal cord. For clarity, the afferent input to the spinal dorsal horn from the site of injury is illustrated as not entering the spinal cord (which it certainly does). input. Temporally, input to the spinal cord likely precedes receipt of similar input in the brain stem, but it may be that other avenues of input (e.g., via the vague) provide an impor- tant (more important?) trigger for the RVM. Returning to the formulation advanced almost 50 years ago by Hardy et al. (1'), we believe that a dominant active influence from the brainstem is necessary for the expression of second- ary hyperalgesia (see Fig. 2~. We acknowledge that there are likely multiple supraspinal sites involved in responding to peripheral tissue insult. Indeed, the limited data available suggest that forebrain sites can play an important role, even if the RVM is the final common pathway of facilitatory influ- ences that mediate spinal neuron excitability. This work was supported by National Institutes of Health awards DA11431 (M.O.U.), NS19912 (G.F.G.), and DA02879 (G.F.G.). 1. Hardy, J. D., Wolff, H. G. & Goodell, H. (1950) J. Clin. Invest. 29, 115-140. 2. Lewis, T. (1936) Clin. Sci. 2, 373-421. 3. Woolf, C. J. (1983) Nature (London) 306, 686-688. 4. LaMotte, R. H., Shain, C. N., Simone, D. A. & Tsai, E. F. P. (1991) J. Neurophysiol. 66, 190-211. 5. Woolf, C. J. (1992) in Hyperalgesia and Allodynia, ed. Willis, W. (Raven, New York) pp. 221-243. 6. Urban, M. O. & Gebhart, G. F. (1998) Prod Brain Res. 116, 407-420. 7. Urban, M. O. & Gebhart, G. F. (1997) J. Neurophysiol. 78, 1550-1562. 8. Urban, M. O. & Smith, D. J. (1993) J. Pharmacol. Exp. Ther. 265, 580-586. 9. Zhuo, M. & Gebhart, G. F. (1992)J. Neurophysiol. 67,1599-1614. 10. Zhno, M. & Gebhart, G. F. (1997) J. Neurophysiol. 78, 746-758. 11. Urban, M. O., Smith, D. J. & Gebhart, G. F. (1996)J. Pharmacol. Exp. Ther. 278, 90-96. 12. Zhuo, M. & Gebhart, G. F. (1990) Brain Res. 535, 67-78. 13. Zhuo, M. & Gebhart, G. F. (1991) Brain Res. 550, 35-48. 14. Almeida, A., Tjolsen, A., Lima, D., Coimbra, A. & Hole, K. (1996) Brain Res. Bull. 39, 7-15. 15. Fields, H. L., Bry, J., Hentall, I. & Zorman, G. (1983) J. Neurosci. 3, 2545-2552. 16. Fields, H. L., Malick, A. & Burstein, R. (1995) J. Neurophysiol. 74, 1742-1759. 17. Fields, H. L., Vanegas, H., Hentall, I. D. & Zorman, G. (1983) Nature (London) 306, 684-686. 18. Bederson, J. B., Fields, H. L. & Barbaro. N. M. (1990) Somato- sens. Res. 7, 185-203. 19. Morgan, M. M. & Fields, H. L. (1994) J. Neurophysiol. 72, 1161-1170. 20. Almeida, A., Tavares, I., Lima, D. & Coimbra, A. (1993) Neu- roscience 55, 1093-1106. 21. Basbaum, A. I., Clanton, C. H. & Fields, H. L. (1978) J. Comp. Neurol. 178, 209-224. 22. Craig, A. D. (1995) J. Comp. Neurol. 361, 225-248. 23. Martin, G. F., Vertes, R. P. & Waltzer, R. (1985) Exp. Brain Res. 58, 154-162. 24. Woolf, C. J. & Wall, P. D. (1986) J. Neurosci. 6, 1433-1442. 25. Woolf, C. J., Shortland, P. & Sivilotti, L. G. (1994) Pain 58, 141-155. 26. Mansikka, H. & Pertovaara, A. (1997) Brain Res. Bull. 42, 359-365. 27. Pertovaara, A. (1998) Exp. Neurol. 149, 193-202. 28. Urban, M. O., Jiang, M. C. & Gebhart, G. F. (1996) Brain Res. 737, 83-91. 29. Urban, M. O., Zahn, P. K. & Gebhart, G. F. (1999) Neuroscience 90, 349-352. 30. Urban, M. O., Coutinho, S. V. & Gebhart, G. F. (1999) Pain 81, 45-55.

OCR for page 7687
7692 Colloquium Paper: Urban and Gebhart Coutinho, S. V., Urban, M. O. & Gebhart, G. F. (1998) Pain 78. 59-69. Melter, S. T. & Gebhart, G. F. (1993) Pain 52, 127-136. Hargreaves, K., Dubner, R., Brown, F., Flores, C. & Joris, J. (1998) Pain 32, 77-88. Sluka, K. A. & Westlund, K. N. (1993) Pain 55, 367-377. Schaible, H.-G. & Schmidt, R. F. (1985) J. Neurophysiol. 54, 1109-1122. 36. Schaible, H.-G., Schmidt, R. F. & Willis, W. D. (1987) Exp. Brain Res. 66, 466-489. 37. Herrero, J. F. & Cervero, F. (1996) Neurosci. Lett. 209, 21-24. 38. Coderre, T. J., Vaccarino, A. L. & Melzack, R. (1990) Brain Res. 535, 155-158. 39. Dubuisson, D. & Dennis, S. G. (1977) Pain 4, 161-174. 40. Bianchi, M. & Panerai, A. E. (1997) Neurosci. Lett. 237, 89-92. 41. Wiertelak, E. P., Furness, L. E., Horan, R., Martinez, J., Maier S. F. & Watkins, L. R. (1994) Brain Res. 649, 19-26. 42. Wiertelak, E. P., Roemer, B., Maier, S. F. & Watkins, L. R. (1997) Brain Res. 748, 143-150. Pro c. Natl. Acad. Sci. USA 96 (1999J 48. 49. 51. 52. 43. Bennett, G. J. (1993) Muscle Nerve 16, 1040-1048. 44. Pertovaara, A., Wei, H. & Hamalainen, M. M. (1996) Neurosci. Lett. 218, 127-130. 45. Bian, D., Ossipov, M. H., Zhong, C. M., Malan, T. P & Porreca, F. (1998) Neurosci. Lett. 241, 79-82. 46. Kauppila, T. (1997) Brain Res. 770, 310-312. 47. Watkins, L. R., Maier, S. F. & Goehler, L. E. (1995) Pain 63, 289-302. Maier, S. F., Wiertelak, E. P., Martin, D. & Watkins, L. R. (1993) Brain Res. 623, 321-324. Watkins, L. R., Wiertelak, E. P., Goehler, L. E., Smith, K. P., Martin, D. & Maier, S. F. (1994) Brain Res. 654, 15-26. 50. Watkins, L. R., Wiertelak, E. P., Goehler, L. E., Mooney- Heiberger, K., Martinez, J., Furness, L., Smith, K. P. & Maier, S. F. (1994) Brain Res. 639, 283-299. Randich, A. & Gebhart, G. F. (1992) Brain Res. Rev. 17, 77-99. Schaible, H.-G., Neugebauer, V., Cervero, F. & Schmidt, R. F. (1991) J. Neurophysiol. 66, 1021-1032. Ren, K. & Dubner, R. (1996) J. Neurophysiol. 76, 3025-3037.