CENTRAL MODULATION OF PAIN PERCEPTION

PAIN MANAGEMENT IN THE RHEUMATIC DISEASES

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CENTRAL MODULATION OF PAIN PERCEPTION Leslie J. Crofford, MD, and Kenneth L. Casey, MD

Pain is a personal subjective experience that varies quite dramatically among individuals in response to an apparently similar stimulus. Pain is defined as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage,"29 but it is important to note that it is an integrative experience associated with consequent behaviors. Pain can be significantly modulated by cognitive, emotional, and environmental factors. Many of the discrete neuronal connections and neurochemicals that contribute to the variability of the pain experience have now been identified. The first attempt to reconcile the clinically observed variability in the response to a noxious stimulus was the gate control hypothesis of Melzack and Wallz7in 1965. These authors made use of the information available on the anatomy and physiology of pain pathways in an attempt to seriously consider variability by focusing on spinal levels. At the time, the concept of a specific pain modulatory system had not yet been formulated," but Reynolds"' and then Mayer et alZ4made the breakthrough observation that stimulation of a specific midbrain region produced analgesia in rats. The clinical significance of this finding was established when electrical stimulation of the same brain region in humans was shown to produce analgesia in some cases.14,32 These early studies also paved the way for understanding the endogenous neurochemical modulation of pain when Mayer and Pricez4hypothesized that opiates and electrical stimulation of certain brain regions acted on the same neuronal pathways. Another intriguing hypothesis posed by From the Division of Rheumatology, Department of Internal Medicine (LJC) and Department of Neurology (KLC), University of Michigan, Ann Arbor, Michigan

RHEUMATIC DISEASE CLINICS OF NORTH AMERICA

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VOLUME 25 NUMBER 1 FEBRUARY 1999

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Fieldsp in 1988 was that there were not only pain inhibition pathways but pain facilitating pathways localized to the same region of the brain. The possibility of bidirectional central control over pain transmission pathways offers further mechanisms that may explain the variability of pain. With an appreciation for the presence of inhibitory and facilitatory control pathways, the question arises as to their physiological function. Why should an intrinsic pain-control system exist if the perception of pain is such an important adaptive mechanism?' The fact that noxious stimuli are generally perceived as painful indicates that such a painsuppressive system is neither easily nor often fully activated. Under some circumstances, however, particularly during strong "drive" states such as fear and aggression with closely associated behavioral correlates, it might be more adaptive to inhibit pain than perceive it. As most of these situations are stressful, it has been suggested that stress is the physiological trigger of the intrinsic pain inhibitory ~ y s t e m . ~ This article discusses the modulation of pain processing by descending control systems. We examine both the anatomical connections that compose the most important descending modulatory pathways and the neurochemical mediators of these phenomena. We discuss activation of modulatory systems by stress. Finally, we consider the clinical implications of pain modulation by these descending pathways. CIRCUITRY OF THE DESCENDING PAIN-CONTROL SYSTEM

The anatomical components of descending pathways that are considered include the periaqueductal gray matter (PAG), the rostroventral medulla (RVM),the dorsolateral (DLF) and ventrolateral funiculi (VLF), the cortical and limbic systems, and paraventricular nuclei of the hypothalamus. This is far from an exhaustive review, but we attempt to focus on the important modulating pathways for pain perception and behaviors. Periaqueductal Gray Matter

The PAG is situated in an excellent position to relay messages from the forebrain to lower brain regions (Fig. l).?It receives inputs from the frontal, cingulate, and insular cortex; limbic system; septum; amygdala; and h y p ~ t h a l a m u s .The ~ ~ input from the cortex to this region may represent cognitive modulation of pain sensation. PAG neurons project to the RVM for relay to the spinal cord. There are also strong projections to the locus ceruleus, where there are noradrenergic neurons with ascending and descending projections.'j Stimulation of the PAG has consistently been reported to relieve pain in animals and in some patients.14,25, 31, 32 The PAG is rich in

CENTRAL MODULATION OF PAIN PERCEPTION

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receptors for opiates and may be critical for the central analgesic effects of these compounds."" The PAG may be a key site for integration of pain behavior and somatomotor adaptation through connections to stressresponse systems and other cortical and subcortical structures." In fact, there is evidence for spatial organization of neurons in the PAG which may be important for behavioral, autonomic, and neuroendocrine responses to painful stimuli localized to different peripheral anatomical sites.19

Rostroventral Medulla The nuclei in the RVM, primarily the nucleus raphe magnus and the laterally adjacent ventral reticular formation, receive projections from the PAG and modulate the transmission of nociceptive messages. Electrical stimulation of neurons in this region produces behavioral analgesia and predominantly inhibits dorsal horn neurons in laminae I, 11, and V which receive input from primary afferent noci~eptors.~, 41 The RVM can also exert a facilitatory effect on pain transmission, however.', 22 The bidirectional control of nociceptive transmission is due to the heterogeneity of RVM neurons with regard to their pain modulatory actions? Fields et al' refer to these RVM neurons as "OFF" cells, which inhibit nociceptive transmission, and "ON" cells, which facilitate transmission. These inhibitory and facilitatory neurons were characterized by the timing of their firing relative to the tail-flick reflex in response to radiant heat.8 OFF cells abruptly pause just prior to the tail flick, and ON cells display accelerated discharge just prior to the tail flick.' When OFF cells are active, tail-flick latencies are long, and when ON cells are active, tailflick latencies are short. Because of the reciprocal actions of these cells, this group of investigators has proposed that ON cells may be interneurons that inhibit OFF cells?

Dorsolateral and Ventrolateral Funiculi In general, inhibition of spinal nociceptive transmission from supraspinal sites occurs via bilateral descending projections in the DLF, and it is thought that facilitatory influences involve the VLE Inhibition but not facilitation is attenuated by unilateral transection and abolished by bilateral transection of the DLE1",42 Direct stimulation of the DLF inhibits spinal nociceptive neurons.26 Inactivation of the VLF, on the other hand, is ineffective in attenuating inhibition, although it decreases facilitation.17.37 There are exceptions to these generalities. Descending inhibition from the locus coeruleus is thought to involve the VLF.17 In addition, the DLF has been implicated in descending facilitation in a model of illness-induced hyperalge~ia.~'

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Mesencephalic

N. locus coeruleus

-

N. gigantocellularis

Rostra1 medulla

- ALF (Sn,SRT, SMT)

Medullary dorsal

--

Caudal Medulla

Cervical Cord

Figure 1. See legend on opposite page

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Cortical and Limbic Systems

The corticospinal pathways originating from the somatosensory cortex are not extensively considered here; however, it must be remembered that the integrative midbrain regions receive input from the somatosensory ~ o r t e x Although .~ poorly defined, the cortical and limbic circuitry that influences cognitive and motivational/emotional input is likely to be crucially important to descending pathways.23These complex and variable parts of the cerebrum send descending input to the PAG and medullary structures. Hypothalamus

Electrical stimulation of the periventricular gray matter, including the medial and lateral hypothalamus, increases the response latency or threshold to noxious stimuli. There seem to be both direct and indirect pathways that mediate this effect. A direct projection of the medial paraventricular nuclei of the hypothalamus to the DLF exists. In addition, oxytocin- and vasopressin-containing neurons of the lateral hypothalamus terminate in dorsal spinal laminae.I3 Both medial and lateral hypothalamic neurons also project directly to the PAG and medullary reticular formation. These pathways represent indirect pathways to the spinal cord by whch hypothalamic nuclei may regulate nociceptive transmi~sion.'~ There is bidirectional signaling between the hypothalamus and midbrain regions which may be responsible for neuroendocrine and behavioral correlates of pain.

Figure 1. Descending endogenous pain modulatory systems. Descending modulatory systems receive input from nociceptive neurons in the spinal cord via the ascending anterolatera1 fasciculus (ALF), which is composed of the spinothalamic (STT), spinoreticular (SRT), and spinomesencephalic (SMT) tracts. The ALF has important inputs into the nucleus raphe magnus (NRM), nucleus reticularis gigantocellularis (NGC), and the periaqueductal gray (PAG) via the nucleus cuneiformis. The ALF also has input to the medullaty/pontine reticular formation, the nucleus raphe dorsalis (NRD), and the mesencephalic reticular formation (MRF). These centers, in turn, modulate the activity of spinal nociceptive neurons. The PAG receives important input from such rostra1 structures as the frontal, cingulate, and insular cortex and other parts of the cerebrum involved in cognition; from the limbic system; the thalamus; and, most importantly, the hypothalamus, which sends p-endorphin axons to the PAG. The locus coeruleus in the pons is a major source of noradrenergic input to the PAG and dorsal horn (tract labeled NE). The mesencephalic structures (PAG, NRD, MRF) contain enkephalin, dynorphin, serotonin, and neurotensin neurons, but only the latter two send axons that project to the NRM and NGC in the rostroventral medulla (RVM). Here, they make synapses with neurons that are primarily serotonergic, whose axons project to the medullary dorsal horn and descend in the dorsolateralfuniculus (DLF) to send terminals to all laminae of the spinal gray (the densest populations are found in laminae I, 110, and V of the dorsal horn and the motor neuron pools of lamina IX). NE fibers also descend and Project to the medullary dorsal horn and then descend in the DLF of the spinal cord to send terminals to laminae I, 110, IV-VI, and X. (from Bonica JJ: Biochemistry and modulation Of nociception and pain. ln Bonica JJ (ed): The Management of Pain, ed 2. Philadelphia, Lea & Febiger, 1990, p 95; with permission.)

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NEUROCHEMISTRY OF DESCENDING CONTROL SYSTEMS

The neurochemical modulators of the descending modulatory pathways that are discussed include serotonin, norepinephrine, opiates, and neurotensin. Although this is but a subset of the mediators involved, the summary represents many of the most important interactions.

Serotonin and Norepinephrine The inhibition of spinal nociceptors by descending pathways is primarily via serotonergic and noradrenergic neurons originating in midbrain and medullary gray matter.3 The cell bodies of serotonincontaining projections are in the nucleus raphe magnus and other nuclei in the RVM. These neurons are thought to provide the serotonergic link in the control exerted from more rostra1 sites in the central nervous system. Norepinephrine-containing neurons of the locus coeruleus contribute projections to the parasympathetic preganglionic column of the sacral cord, and neurons in other medullary nuclei contribute axons to sympathetic preganglionic neurons of the thoracic cord.3 Evidence that serotonin and norepinephrine represent the final pathway for descending inhibitory control was summarized by Yak~h.~O Activation of bulbospinal pathways that contain norepinephrine or serotonin inhibits spinal nociceptive activity. In addition, enhancement of spinal monoamine receptor activity by local delivery of a,-adrenergic or serotonin agonists inhibits pain behavior, although the spinal action of these agonists inhibits the firing of dorsal horn neurons evoked by high-intensity stimuli. Noradrenergic neurons also project to the R v I ~ l . 2It~ can be shown that stimulation through the &,-receptor excites ON cells and correlates with behavioral hyperalgesia, although au,-receptoragonists inhibit ON cells leading to antinociception.28The predominant effect of norepinephrine itself is a long-lasting a,-mediated antinociceptive effect. Although direct application of norepinephrine to OFF cells has neither an inhibitory nor excitatory effect, tyrosine hydroxylase-containing appositions whose functional significance remains unclear are seen.2s

Opiates Opiate receptors are concentrated in several well-defined regions of the brain, prominently including those regions involved in descending control of nociception, the PAG and RVM.40Morphine and endogenous opioids produce antinociception and analgesia in descending modulatory circuits by activating p opiate receptors in these regions.40The opiate receptors and their ligands are listed in Table 1.There is evidence of interactions between these receptor-ligand pairs. For example, K opiate receptor agonists antagonize receptor-mediated analgesia in RVM

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Table 1. OPlOlDS AND OPlOlD RECEPTORS ~

~

Prohormone

Proopiomelanocortin Proenkephalin A

Proenkephalin B

Peptide (Amino Acids)

P-Endorphin (31) y-Endorphin (17) Leu-enkephalin (5) Met-enkephalin (5) Heptapeptide (7) Methorphamide (7) Dynorphin (17) Dynorphin,, ( 8 ) a-Neoendorphin (10) Dynorphin B (13)

~

Recevtor

~

Naloxone Sensitivitv

E

Weak

6

Weak

8 P. K

Strong Intermediate

Datn froni Bonica JJ: Biochemistry and modulation of nociception and pain. In Bonica JJ (ed): The Management of Pain, ed 2. Philadelphia, Lea & Febiger, 1990, p 95; and Yaksh TL: Pharmacology and mechanisms of opioid analgesic activity. Acta Anaesthesiol Sand 41:94, 1997.

cells.3O The opposing effect on ~ 1 .of the K receptor extends to opioid actions on emotion, perception, and drug reinforcement. Although morphine and other p agonists produce euphoria and place-preference, K receptor agonists cause dysphoria and aversion. Morphine-like opioids possess the property of being rewarding and increase dopamine release in the mesolimbic system, whereas K agonists block morphine-induced rewarding effects.30 Activity of opiates in the midbrain and brain stem enhances release of norepinephrine and serotonin in the dorsal horn, which accounts for much of the antinociceptive and analgesic activity of these compounds. Opiate microinjection into brain stem sites such as the PAG increases the spinal release or turnover of serotonin or norepinephrine.4O Intrathecal injection of ol,-noradrenergic or serotonergic antagonists has minimal effects on resting baseline response latencies but reverses the effects of PAG opiate microinjection on spinal reflexes and analgesia.4o

Neurotensin Neurotensin is a tridecapeptide that can mediate descending modulatory pathways by acting on neurons in the PAG and RVM. There is a large neurotensinergic projection from the ventrolateral part of the PAG to the nucleus raphe magnus of the RVM.’, Although originally characterized as mediating antinociception, neurotensin is now recognized as having a biphasic effect, as injection of lesser doses facilitates the tailflick reflex and larger doses inhibit the same reflex when injected in the RVM.37 There is evidence of interaction between neurotensin and the serotonergic descending modulatory pathways.16 It has been suggested that nonopioid stress analgesia is mediated via neurotensin.

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INTERACTIONS BETWEEN STRESS AND PAIN PATHWAYS Stress-Induced Analgesia

The awareness of pain normally impels adaptive action essential for survival, and an analgesia system therefore ought not to be activated trivially.36In contrast, under emergency or stressful conditions, when pain perception could disrupt effective coping, pain inhibition would be more adaptive. As previously stated, it is thought that stress is a natural or physiological trigger of the intrinsic pain inhibitory ~ y s t e m .The ~ phenomenon of stress-induced analgesia involves both opioid- and nonopioid-mediated mechanisms, usually classified on the basis of sensitivity to naloxone or cross-tolerance with Both opioid and nonopioid stress-induced analgesia is disrupted by lesions of the spinal DLF (see Fig. l), suggesting involvement of descending inhibitory pathways.20 The mechanisms underlying stress-induced analgesia, particularly nonopioid forms, are not fully understood. Experimental evidence suggests that enkephalins produced in the adrenal medulla mediate one opioid form of stress-induced analge~ia.~ Stress also induces production of P-endorphin in the pituitary gland. Recent experimental evidence using mice in which the P-endorphin gene has undergone targeted disruption demonstrates that mutant mice lack the opioid (naloxonereversible) stress analgesia but display significantly greater nonopioid analgesia.33These data suggest that there may be compensatory upregulation of alternative pain inhibitory mechanisms when opioid-dependent pathways are impaired or eliminated.33 Further evidence of the interactions between pain inhibitory pathways and stress systems comes from demonstrations that corticotrophin prevents the development of tolerance to morphine analgesia'O and stress blocks the development of morphine tolerance in intact but not adrenalectomized mice.35Both adrenalectomy and hypophysectomy potentiate the magnitude of opiate tolerance, with the effect of hypophysectomy being reversed by replacement of corti~otrophin.~~ Using inbred rat strains that exhibit differences in hypothalamic-pituitary-adrenal (HPA) axis responsiveness to many types of stress, Vaccarino and CoureP showed that genetic differences in stress-response systems influence descending inhibitory pathways. Sternberg et a P demonstrated that Lewis rats had blunted activation of the HPA axis in response to many different types of acute stress, although Fischer rats exhibited a robust increase in plasma corticotrophin and corticosterone in response to the same stimuli. Both strains developed tolerance to morphine in the absence of pain; however, the presence of pain during morphine administration prevented the development of analgesic tolerance in Fischer but not Lewis rats.38These authors suggested that genetic differences in stress-induced HPA axis activity may play a role in the development of tolerance to morphine analgesia?* By analogy, these stress

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systems may influence the activity of descending inhibitory and facilitatory pain pathways.

Integration of Pain Pathways and Stress-Response Systems

Any painful stimulus activates both sympathetic and HPA axis stress systems.15The reactions of these systems are closely linked to arousal reactions as well as to the affective/emotional dimension of pain. The reactions enable the organism to cope with painful situations and are presumably protective or adaptive under normal biological conditions. There is evidence provided by Keay and BandleP and Keay et ally of functional and anatomical organization within the PAG (Fig. 2). These investigators have hypothesized that pain behaviors in response to different noxious stimuli may be integrated in this midbrain region. As early as 1942, Lewisz1called attention to different behavioral patterns

confrontationaldefense regional blood flow:

regional blood flow limbs 4 viscera face 4

4

Ventrolateral PAG

quiescence hyporeactivity hypotension bradycardia opioid analgesia

Figure 2. Defensive and quiescent behavior in the lateral and ventrolateral periaqueductal gray (I-PAG, vI-PAG). Lateral and ventrolateral columns within the rostral, intermediate, and caudal PAG. The dorsomedial and dorsolateral neuronal PAG columns are indicated in interrupted contours. Stimulation of neuron populations in the I-PAG and vI-PAG by microinjections of excitatory amino acids evokes distinct behaviors and the corresponding autonomic (changes of blood flow, blood pressure, heart rate) and sensory (analgesia) changes-confrontational defense from the intermediate I-PAG, flight from the caudal IPAG; quiescence (cessation of spontaneous activity) from the vI-PAG. (From Bandler R, Shipley MT: Columnar organization in the midbrain periaqueductal gray: Modules for emotional expression? Trends Neurosci 17:379-389, 1994; with permission.)

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evoked by pain arising from superficial (skin) and deep tissues (muscles, joints, viscera). Whereas pain from cutaneous stimulation was associated with quick protective reflexes, a rise in pulse rate, and a sense of invigoration, pain arising from deep structures was usually associated with quiescence, slowing of the pulse, a fall in blood pressure, and 21 These same neuroendocrine, loss of interest in the en~ironment.’~, autonomic, and behavioral patterns can be mimicked by stimulation of certain areas of the PAG. Direct excitation of cells in the lateral PAG column evokes active defensive behaviors such as confrontation or flight, vocalization, hypertension, and tachycardia, although excitation of cells in the ventrolateral PAG evokes quiescence, hyporeactivity, hypotension, and bradycardia, resembling reactions typical of deep pain.19 These investigators went on to demonstrate that noxious stimulation to deep somatic structures stimulates neuronal activity, measured by increased c-fos immunoreactivity, in the ventrolateral PAG.18,lYThis stands in contrast to cutaneous noxious stimulation which leads to increased c-fos immunoreactivity in more lateral areas of the PAG.lS,j 9 This same group of investigators made the observation that deep pain causes activation of the HPA stress axis, measured by corticotrophin levels, at the same time that the ventrolateral PAG was activated? The ventrolateral PAC sends direct projections to the paraventricular nucleus of the hypothalamus.” These projections terminate on the medial parvocellular nuclei that control neuroendocrine output by secretion of corticotropin releasing hormone and arginine vasopressin which subsequently activate pituitary-adrenal stress hormone production. Projections also terminate in the magnocellular divisions of the paraventricular hypothalamus which stimulate vasopressin release from the posterior pituitary gland.” In addition, neurons of the PAG can project to medullary structures that contain parasympathetic and “presympathetic” neurons involved in regulating different types of autonomic target organ^.'^ Based on the evidence presented above, the PAG has been proposed as the site for integration of pain sensation, pain behaviors, and neuroendocrine adaptation to pain.3, lYNoxious events occurring on the body surface and deriving from the environment are associated with active coping strategies such as defensive confrontation or flight.15In contrast to cutaneous pain, which often can be controlled to some extent by the animal and from which the animal may be able to escape, deep pain is both inescapable and usually impossible for the animal to actively behaviorally Therefore, noxious events in the deep body domains are associated with more passive coping strategies.lSA quiescent and hyporeactive response may represent one way for the animal to reduce discomfort and limit interactions that might increase pain. It is of interest to note that a similar reaction of quiescence and loss of interest in the environment is characteristic of chronic pain and is commonly observed in animals that have been defeated or injured in a social encounter.”

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Environmental Influences One adaptive response to stress or pain is learning to associate neutral environmental cues accompanying or preceding the stimulus with its aversive qualities.’ For example, placing rats in a cage where electrical foot shock was previously administered elicits many responses formerly seen during the shock presentation, one of which is analgesia.’ Evidently, animals can activate their intrinsic pain lnhibitory systems not only in the presence of pain but also in anticipation of a painful stimulus.2Not only can pain inhibitory pathways be activated by conditioning or anticipation, but animals can also learn to activate paintransmitting dorsal horn neurons. Experiments by Duncan5 demonstrated this phenomenon in primates. Monkeys were trained to press a lever after a light cue. When the lever was pressed, a noxious heat stimulus was delivered to the skin. Dorsal horn cells that responded maximally to this noxious stimulation projected to the thalamus, demonstrating characteristics of pain-transmission neurons. Some of these cells had a clear-cut discharge when the light cue was delivered, which was long before any noxious stimulus was applied. Ciearly, some paintransmitting neurons can be activated by behavioral contingencies, perhaps by stimulating ON cells in the RVM.3

Clinical Implications

It is clear that pain cannot be viewed simply as a stimulus followed by a unitary response. The neurons that transmit pain from the spinal cord can be significantly influenced by extrinsic input. It follows that management of pain must take into account not only the physical/ anatomical stimulus for pain but also the factors that influence the pain experience of each individual patient. The issue, as framed by H.L. Fields,8 remains that “What is quite clear is that with apparently similar stimuli some patients complain bitterly; others deny that the experience is painful at all. One point of view is that both feel the same thing but that one is a complainer and the other a stoic. Another idea is that they actually feel different intensities of pain and that both are responding appropriately.” Putting aside the sensation of pain, it is clear that the behavioral response to pain is malleable.8* Patients can be taught to diminish pain complaints, increase function, and decrease the amount of drugs taken.l2 It is also likely that patients can learn to increase pain complaints and behaviors, which is possibly the etiology of the psychogenic pain syndrome? What remains uncertain is whether behavioral changes are associated with an actual change in the neuronal activity that transmits the pain signal in humans. If there is a change, it is likely mediated by descending modulatory pathways. Evidence suggests that these pathways can both inhibit and facilitate neuronal activity. Most important to clinical practice is understanding how these pathways function in chronic pain.

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SUMMARY

The information presented in this article provides a basis for individual variability in the sensation of pain and the behavioral correlates associated with pain. The knowledge of pain-inhibitory and pain-facilitating pathways linked to cognitive, emotional, and stress-response systems leads to a greater understanding of the complexities of the experience of pain. Appreciation of the influence of these higher centers should lead to improvements in the clinical management of pain.

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20. Lewis JW, Cannon JT, Liebeskind JC: Opioid and nonopioid mechanisms of stress analgesia. Science 208623, 1980 21. Lewis T Pain. London, McMillan, 1942 22. Light AR, Casale EJ, Nenetrey DM: The effects of focal stimulation in nucleus raphe magnus and periaqueductal gray on intracellularly recorded neurons in spinal laminae I and 11. J Neurophysiol56:555, 1986 23. Mantyh PW: Forebrain projections to the periaqueductal gray in the monkey, with observations in the cat and rat. J Comp Neurol 206146, 1982 24. Mayer DJ, Price D D Central nervous system mechanisms of analgesia. Pain 2379,1976 25. Mayer DJ, Akil H, Liebeskind JD: Pain reduction by focal electrical stimulation of the brain: An anatomical and behavioral analysis. Brain Res 68:73, 1974 26. McMahon SB, Wall P D Descending excitation and inhibition of spinal cord laminae 1 projection neurons. J Neurophysiol 591204, 1988 27. Melzack R, Wall PD: Pain mechanisms: A new theory. Science 150:971, 1965 28. Meng X-W, Budra B, Skinner K, et a1 Noradrenergic input to nociceptive modulatory neurons in the rat rostral ventromedial medulla. J Comp Neurol377381, 1997 29. Merskey H, Bogduk N Classification of Chronic Pain, ed 2. Seattle, International Association for the Study of Pain (IASP) Press, 1994 30. Pan ZZ, Tershner SA, Fields HL: Cellular mechanism for anti-analgesic action of agonists of the K-opioid receptor. Nature 389:382, 1997 31. Reynolds DV Surgery in the rat during electrical analgesia induced by focal brain stimulation. Science 164444, 1969 32. Richardson DE, Akil H Pain reduction by electrical brain stimulation in man. Part 2: Chronic self-administration in the periventricular gray matter. J Neurosurg 74:184, 1977 33. Rubenstein M, Mogil JD, Japon M, et al: Absence of opioid stress-induced analgesia in mice lacking p-endorphin by site-directed mutagenesis. Proc Natl Acad Sci U S A 93:3995, 1996 34. Stemberg EM, Young WS 111, Bernardini R, et al: A central nervous system defect in biosynthesis of corticotropin-releasing hormone is associated with susceptibility to streptococcal cell wall-induced arthritis in Lewis rats. Proc Natl Acad Sci U S A 86:4771, 1989 35. Takahashi M, Sugimachi K, Kaneto H: Role of adrenal glucocorticoids in the blockade of analgesic tolerance to morphine by footshock stress exposure in mice. Jpn J Pharmacol 51:329, 1989 36. Terman GW, Shavit Y, Lewis JW, et al: Intrinsic mechanisms of pain inhibition: Activation by stress. Science 2261270, 1984 37. Urban MO, Gebhart G F Characterization of biphasic modulation of spinal nociceptive transmission by neurotensin in the rat rostral ventromedial medulla. J Neurophysiol 78:1550, 1997 38. Vaccarino AL, Couret LC: Relationship between hypothalamic-pituitary-adrenal activity and blockade of tolerance to morphine analgesia by pain: A strain comparison. Pain 63:385, 1995 39. Watkins LR,Wiertelak EP, Goehler LE, et a1 Neurocircuitry of illness-induced hyperalgesia. Brain Res 639283, 1994 40. Yaksh TL: Pharmacology and mechanisms of opioid analgesic activity. Acta Anaesthesiol Scand 41:94, 1997 41. Zagon A, Meng X, Fields HL: Intrinsic membrane characteristics distinguish two subsets of nociceptive modulatory neurons in rat RVM. J Neurophysiol 78:2848, 1997 42. Zhuo M, Gebhart GF: Characterization of descending facilitation and inhibition of spinal nociceptive transmission from the nuclei reticularis gigantocellularis and gigantocellularis pars alpha in the rat. J Neurophysiol 67:1599, 1992

Address reprint requests to Leslie J. Crofford, MD University of Michigan Medical Center Room 5510E, MSRB I 1150 West Medical Center Drive Ann Arbor, MI 48109-0680