Interactions between cardiovascular and pain regulatory systems

Neuroscience &BiobehavioralReviews, Vol. 8, pp. 343-367, 1984. ©AnkhoInternationalInc. Printed in the U.S.A.

0149-7634/84$3.00 + .00

Interactions Between Cardiovascular and Pain Regulatory Systems ALAN RANDICH 1

Department o f Psychology, The University o f Iowa and WILLIAM MAIXNER 2

Department o f Pharmacology, The University of Iowa R e c e i v e d 11 July 1981 RANDICH, A. AND W. MAIXNER. Interactions between cardiovascular and pain regulatory systems. NEUROSCI BEHAV REV 8(3) 343-367, 1984.--A review of pharmacological, neuroanatomical, electrophysiological, and behavioral data indicates that systems controlling cardiovascular function are closely coupled to systems modulating the perception of pain. This view is directly supported by experiments from our laboratory showing that activation of either the cardiopulmonary baroreceptor reflex arc or the sinoaortic baroreceptor reflex arc induces antinociception. The outcomes of studies using pharmacological treatments, peripheral nerve stimulation, peripheral nerve resection, and CNS lesions are also presented as a preliminary means of characterizing cardiovascular input to pain regulatory systems. The network formed by these systems is proposed to participate in the elaboration of adaptive responses to physical and psychological stressors at various levels of the neuroaxis, and possibly to participate in "diseases of adaptation." In particular, the present analysis suggests that the inhibition of pain brought about by elevations in either arterial or venous blood pressure may provide a form of psychophysiologicai relief under situations of stress and contribute to the development of essential hypertension in humans. Cardiovascular regulation Pharmacology

Pain regulation

Behavior

DYNAMIC physiological systems capable of reacting to physical and psychological demands made upon the body (stressors) are vital for the existence of an organism. Reactions to stressors typically involve either short- or long-term compensatory responses that tend to maintain adequate physiological function in the face of the imbalance created by the stressor [47]. For example, the cardiovascular diving reflex is evoked by submersion of the organism in water, and results in both profound bradycardia and vasoconstriction of all peripheral vascular beds. The net effect of this stressinduced reflex adjustment is to limit myocardial oxygen demands and shunt blood centrally for maximal oxygen delivery to the vital organs. Neurogenic and neurohumoral systems have figured prominently in the analysis of reactions to stressors [46, 48, 175,223,224], but beyond a basic understanding of simple reflex adjustments, derived from studying systems in isolation, we know very little about the manner in which different systems coordinate their responses to a stressor and operate collectively in the intact organism. Moreover, when the intensity or the duration of the requisite adjustment exceeds the limits of these adaptive mechanisms, pathological changes may ensure. Selye [223,224] called these changes "diseases of adaptation," and they may in-

Neuroanatomy

Electrophysiology

clude such disease entities as hypertension, gastric ulceration, and mental disorders. It is important, therefore, to determine the extent to which physiological systems interact with one another in coordinating responses to stressors. A basic understanding of such interactions should facilitate analysis of factors associated with the onset and maintenance of "diseases of adaptation." The present paper approaches this goal by asserting that peripheral and central systems involved in cardiovascular regulation are physiologically linked to systems involved in pain perception to form a functional network governing the elaboration of adaptive responses to physical and psychological stressors. The weak form of this hypothesis will be supported by pharmacological, neuroanatomical, electrophysiological, and behavioral data showing strong correlations between cardiovascular function and the perception of pain. The strong form of this hypothesis will be supported primarily by experiments from our laboratory showing that input from peripheral baroreceptors changes pain sensitivity. Specifically, these experiments show that antinociception is induced by elevations in either central venous pressure or arterial blood pressure. Finally, the potential role of the network

~Requests for reprints should be addressed to Alan Randich, Department of Psychology, The University of Iowa, Iowa City, IA 52242. 2W. Maixner is currently in the Neurobiology and Anesthesiology Branch of the National Institute of Dental Research.

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344 formed by cardiovascular and pain regulatory systems is discussed in terms of the etiology of essential hypertension in humans. E N D O G E N O U S SYSTEMS M E D I A T I N G I N H I B I T I O N OF PAIN

The existence of endogenous systems in the CNS capable of inhibiting pain was originally suggested by findings that electrical stimulation of periaqueductal and pontine central grey produced analgesia (stimulation produced analgesia: SPA), but little else was known about the nature of such systems. It soon became evident, however, that strong parallels existed between the analgesia induced by morphine administration and that produced by stimulation of the periaqueductal and pontine central grey; thereby implicating a possible common neural substrate of pain modulation. Some of the parallels between SPA and morphine-induced analgesia include (1) selective inhibition of nociceptive cells in lamina V of spinal cord, nucleus reticularis gigantocellularis, and nucleus oralis or trigeminal nerve [89, 146, 153, 159, 176, 219, 240], (2) comparability of analgesic action [167], (3) tolerance with repeated administration and partial cross-tolerance [166, 187], (4) reversal or attenuation by opioid receptor antagonists [6], (5) attenuation by lesions of the dorsolateral funiculus and nucleus raphe magnus [ 19,199], (6) neuroanatomical overlap of loci associated with SPA and morphine-induced analgesia (see [168,267] for reviews), and (7) similar neurohumoral effects; many monoaminergic and peptidergic similarities have been reported for these two forms of analgesia [4, 54, 88, 168, 199, 267]. The subsequent isolation and characterization of endogenous opioid peptides [26, 68, 106, 123, 124], collectively referred to as the endorphins and enkephalins, and demonstrations that opioid receptors have similar regional distributions as the endorphins and enkephalins [13, 14, 15, 228, 247] permitted preliminary characterization of the structure and function of an endogenous pain inhibition system in which opioids are a major component [see 9, 18, 54, 88, 168, 171, 267 for reviews]. On the basis of this research, Fields and Basbaum [88] proposed a normally inactive pain inhibition system involving a monosynaptic serotonergic pathway which originates in the nucleus raphe magnus and travels in the dorsolateral funiculus of spinal cord to synapse with various structures in the substantia gelatinosa and lamina V of the dorsal horn. SPA presumably results from activating this system via a central grey pathway projecting to the nucleus raphe magnus [19]. It should be noted, however, that others have argued for tonically active systems [227]. Recent data also indicate a role for other medullary structures and neurotransmitters in SPA [87,98], although it is not clear if these represent separate systems or part of the local medullary circuitry of the system described above. These medullary areas include nucleus reticularis gigantocellularis [176,177] and nucleus reticularis paragigantocellularis [258]. Substance P, glutamate, and other catecholamines may also be important transmitters [49, 98,267]. Indeed, based upon recent pharmacological and lesion studies by Proudfit and his colleagues [112, 113, 197, 198,216], and electrophysiological studies of Wolstencroft [265], the notion of a descending serotonergic pain inhibitory spinal pathway must be supplemented to include other descending pain inhibitory pathways, e.g., a noradrenergic pathway. Studies have also suggested the existence of systems capable of inhibiting pain in which endogenous opioids ap-

RANDICH AND MAIXNER pear to play no role (see [54,267] tbr reviews). This view is based upon observations that (1) not all forms of SPA are reversed by opioid receptor antagonists [192,268], although to a large extent this issue is confounded by our lack of understanding about opioid receptor mechanisms [75, 221, 252], and (2) a complete anatomical overlap does not exist between various types of analgesia induced by morphine and SPA [152,267]. In addition, research on stress-induced analgesia reinforced the view that opioid and non-opioid pain inhibition systems act either separately or in concert in the modulation of pain perception [9, 29, 54, 151, 161. 168]. Stress-induced analgesia occurs in animals as a result of exposure to a variety of stimuli including inescapable tail- or foot-shock, immobilization, centrifugal rotation, forced cold water swim, and food deprivation [8, 30, 31, 33, 34, 59, 62, 100, 115, 117, 149, 150, 168, 212, 257]. Stress-induced analgesia has also been demonstrated in man [262,263]. Extensive reviews of stress-induced analgesia are already available, but the following examples have been advanced as lines of evidence supporting the existence of non-opioid pain inhibition systems. For example, analgesia resulting from a brief exposure to shock, e.g., 3-min of continuous stimulation, (1) is not affected or only partially affected by opioid receptor antagonists [5, 55, 103, 115], (2) does not alter central met-enkephalin levels [94], (3) does not show crosstolerance with morhpine [56], (4) fails to be affected by spinal cord lesions that attenuate morphine-induced analgesia [19,117], and (5) has a time-course which differs from that produced by enkephalin administration [4, 117, 160]. In addition, originally neutral environmental stimuli associated with foot-shock acquire the capacity to evoke analgesia as a conditioned response [57], but in some investigators hands, the conditioned analgesia is neither dependent upon the integrity of the pituitary-adrenal axis nor affected by opioid receptor antagonists [54]. Additional independent evidence for the existence of non-opioid pain inhibition systems derives from the work of Bodnar and colleagues on stressinduced analgesia following cold water swim [27, 28, 29, 31, 32, 37, 100]. A potential non-opioid pain inhibition system may involve a descending oxytocin-vasopressin pathway originating in the paraventricular nucleus of the hypothalamus projecting to both the brain stem and spinal cord (see [37, 174, 238] for considerations). Vasopressin and analogues of vasopressin administered via intravenous, subcutaneous, or intracerebroventricular routes induces analgesia in tail-flick, abdominal constriction, and hot-plate assays of pain sensitivity [23, 24, 25, 135]. The analgesia can be reversed following administration of a vasopressin antagonist [23], but not following administration of opioid receptor antagonists [23, 24, 25]. Moreover, these analgesic effects do not appear to be related to any peripheral pressor action of vasopressin [23, 25]. In agreement with this contention, vasopressin-deficient Brattleboro rats are reported to be more sensitive to noxious electric foot-shock than controls, and this effect is reversed by systemic administration of vasopressin analogues [27,29]. In summary, opioid and non-opioid systems probably exert control over the transmission of information about painful stimuli, and the delineation of these systems is just in preliminary stages. CARDIOVASCULAR R E G U L A T I O N : BARORECEPTOR R E F L E X ARCS

The following section presents basic material regarding cardiovascular reflexes, and in particular, peripheral

C A R D I O V A S C U L A R A N D PAIN I N T E R A C T I O N baroreceptor mediated adjustments of cardiovascular function. This aspect of cardiovascular function is addressed specifically since it bears directly upon the hypothesis of cardiovascular-pain regulatory interactions to be proposed later. Excellent reviews of all aspects of cardiovascular function are available elsewhere [71, 92, 97, 136]. One major source of integration of cardiovascular function is provided by the baroreceptor reflex arcs. Mechanoreceptors located in the walls of the carotid sinuses, aortic arch, carotid arteries, and the bifurcation of the brachiocephalic and subclavian arteries respond to mechanical distention to increase afferent activity in the carotid sinus nerves and aortic depressor nerve. Collectively, these mechanoreceptors are referred to as high pressure baroreceptors, and they primarily modulate the system variable of arterial blood pressure. Activation of these baroreceptors by an increase in arterial blood pressure brings about compensatory responses which include an increase in vagal tone and a withdrawal of sympathetic tone, or more generally, engagement of the sinoaortic baroreceptor reflex arc. Similarly, mechanoreceptors located in the heart and lungs respond to mechanical distension to increase afferent activity in the vagi. Collectively, these mechanoreceptots are referred to as low pressure baroreceptors, and they are important for regulating body fluid balance. Although activation of these baroreceptors brings about compensatory adjustments, e.g., as in response to volume expansion, the nature of the changes critically depend upon the specific population of receptors activated. This system is collectively referred to as the cardiopulmonary baroreceptor reflex arc. The primary afferents from the high and low pressure baroreceptor reflex arcs, i.e., carotid sinus, aoritc depressor, and vagal nerves, are believed to have their first synapse predominantly in nucleus tractus solitarius (NTS) of the medulla. There is a great deal of disagreement concerning secondary neurons of these reflex arcs, but pathways are generally believed to be polysynaptic and project to structures such as dorsal vagal nucleus, nucleus reticularis lateralis, nucleus ambiguus, and nucleus reticularis gigantocellularis [189]. Ultimately, the efferent limb of these reflex arcs innervates cell bodies in the medulla and spinal cord which give rise to preganglionic vagal and sympathetic fibers, respectively. It is also important to note that supramedullary structures are integrally tied to these arcs as will be discussed later. I N T E R A C T I O N S B E T W E E N C A R D I O V A S C U L A R AND PAIN R E G U L A T O R Y SYSTEMS

Historically, the view that systems subserving cardiovascular function interact with systems subserving pain perception was anticipated by a variety of findings showing that activation of the high pressure baroreceptor reflex arc resulted in "generalized inhibitory" effects, although at the time these effects were not considered in terms of alterations in pain perception. F o r example, distension of the carotid sinus region, which activates the high pressure baroreceptors reflex arc, was reported to (1) decrease muscle tone in anesthetized dogs [245], (2) diminish cortical activity in anesthetized dogs [38], (3) induce a "sleep-like" state in conscious dogs [134], and (4) depress orthodromically evoked discharges of pyramidal tract cells in pericruciate cortex of cats [63]. Sham-rage was inhibited by activation of the high pressure baroreceptor reflex arc in decerebrate cats, whereas bilateral common carotid artery occlusion (which reduces ongoing activity of the carotid sinus nerve) aug-

345 mented sham-rage reactions in these animals [16]. In a similar manner, convulsions are inhibited by either mechanical stimulation or drug-induced activation of sinoaortic baroreceptors, whereas convulsions are augmented when sinoaortic pressure is lowered [99]. Finally, cortical excitation and inhibition resulting from the administration of hypotensive and hypertensive acting drugs are greatly diminished or abolished following deafferentation of the sinoaortic baroreceptors [179]. Thus, a collection of diverse phenomena were demonstrated by altering the function of the high pressure sinoaortic baroreceptor reflex arc. More substantive support for the view that cardiovascular systems interact with pain regulatory systems can be derived from studies using pharmacological manipulations. Peripheral administration of a-sympathomimetic pressor agents in doses capable of increasing arterial blood pressure and activating the high pressure baroreceptor reflex arc, e.g., phenylephrine, norepinephrine, methoxamine, and 2aminoindane, induce hypoalgetic behaviors in the rat as assayed by the inflamed foot pad, writhing, or hot-plate assays of pain sensitivity [64, 138, 154]. Moreover, in at least some of these studies, the hypoalgesia was not related to elevation or lowering of body temperature, piloerection, exophathalamus, or lowering of the skin temperature in the foot [64]. In general, most of these studies favored the view that sympathomimetics induced hypoalgesia by acting directly on the central nervous system (CNS), rather than acting at a peripheral site with afferent neural input to the CNS. Experiments which bear upon this interpretation will be presented later. However, it should be recalled that a sympathomimetically-induced elevation in arterial blood pressure will engage the baroreceptor reflex arc which, in turn, will promote an increase in vagal tone and a decrease in sympathetic tone. It is also interesting to note that sympathomimetics have often been used as analgesics in humans [85]. Other pharmacological agents which stimulate the baroreceptor reflex arc by peripheral mechanisms, such as capsaicin, nicotine, and the veratrum alkaloids, also produce a profound antinociception [1, l l 4 , 129, 164, 217,243,255, 266]. However, at least with capsaicin administration, the analgesic effect critically depends upon the route of administration and type of pain assay used [35,254,266]. It remains to be determined to what extent these forms of analgesia are mediated by baroreceptor stimulation, but experimental evidence from our laboratories will be presented later which bear on this issue. Analogous to the peripheral cardiovascular effect of baroreceptor activation following administration of sympathomimetics, e.g., reflex bradycardia, systemic administration of endorphinomimetic compounds reduces resting blood pressure and heart rate in variety of species, and of course, induces analgesia [84, 90, 145, 147]. It is generally believed that these compounds act directly in the CNS to engage the efferent limb of the baroreceptor reflex arc, although at least some endorphinomimetic compounds, e.g., fentanyl and morphine, are proposed to exert their cardiovascular effects by facilitating the input and transmission of baroreceptor impulses through the nucleus tractus solitarius [143]. Microinjection of fl-endorphin into the NTS promotes a gradual decrease in both arterial blood pressure and heart rate in rats, and these effects are blocked by prior administration of naloxone [72]. Moreover, a serotonergic pathway is believed to be important for the hypotensive actions of systemically administered fl-endorphin, since pretreatment with the serotonin depleter p-chlorophenylalanine

346 or administration of serotonin antagonists (cyproheptadine, mianserin, and metergoline) wither, attenuate or eliminate the hypotension [ 147]. This potential role of serotonin is of interest, since one of the descending sympatho-inhibitory pathways of the cardiovascular system originates in B3 region of Dahlstrrm and Fuxe [69,70], and courses in the dorsolateral funiculus to the intermediolateral cell columns [17, 43, 121, 157]. It should be recalled that a centrifugal pain inhibition pathway has been described that traverses the same area as this cardiovascular pathway. Endorphins have also figured prominently in the pathophysiology of hemorrhagic shock as shown by the excellent work of Holaday and Faden, and their colleagues [79,251], although this work will not be reviewed here. The cardiovascular effects of enkephalinergic compounds vary considerably as a function of both the compound and the site or route of administration. Intravenous administration of leu- and met-enkephalin induces a short-lasting increase in blood pressure in rats (less than 1 min), but heart rate increases are only observed with met-enkephalin administration [229]. Similar results have been reported in spontaneously hypertensive rats (SHRs) and Wistar-Kyoto normotensive rats (WKYs) for short-lasting pressor effects of leu-enkephalin [222], but this study also reported heart rate increases for leu-enkephalin not found in the previous study. In pentobarbital-anesthetized cats, however, intravenous administration of leu-enkephalin results in a transient increase in arterial blood pressure followed by a sustained hypotension, whereas met-enkephalin induces only hypotension [178]. Neither agent significantly altered heart rate or central venous pressure in this study. Microinjection of D-Ala 2, Met-'~enkephalin into the NTS evokes an increase in arterial blood pressure and heart rate [72]. Similarly, met- and leu-enkephalin induce marked increases in blood pressure and heart rate when infused into the lateral ventricles or cisterna magna of rats, and the blood pressure increases were attenuated by prior treatment with propanolol [222,229]. However, in this study [229], only the met-enkephalin-induced increases in heart rate were attenuated by propanolol treatment. However, administration of D-ala~-met-enkephalinamide into the cisterna magna of dogs resulted in initial pressor and tachycardic responses followed by long-lasting depressor and bradycardic responses [ 144]. Similarly, administration of putative enkephalin releaser veratridine, L-Try-D-Arg or physostigmine into the nucleus ambiguus of chloralosed dogs induced a naloxone-reversible bradycardia [144]. Thus, both endorphinergic and enkephalinergic compounds exert profound cardiovascular changes, although the precise nature of these changes depend upon the route of administration, site of central injection, and the time period monitored following the injection. Notice, however, that none of these studies provide evidence about possible analgesic effects of these opioids. Clonidine, an a-adrenoreceptor agonist, also produces hypotensive and antinociceptive responses following either peripheral or central administration. Endogenous opioid and non-opioid mechanisms have been implicated in the hypotensive actions of clonidine since naloxone treatment attenuates the antihypertensive properties in the spontaneously hypertensive rat. In addition, clonidine has been shown to enhance the release of fl-endorphin-like material from medullary structures of the SHR [82, 83, 139]. Like many of the opioid-like substances, clonidine interacts with various components of the baroreceptor reflex arc and with

R A N D I C H A N D MA1XNER various supramedullary structures which modulate baroreceptor function. In addition to its' antihypertensive effects, clonidine produces an antinociception which does not appear to involved endogenous opioids, since naloxone fails to alter clonidine-induced analgesia of (1) mice in tail-flick and phenylquinone writhing assays [86], and (2) rats in pawpressure and tail-withdrawal assays of pain sensitivity [86,188]. Interestingly, cross tolerance is observed between clonidine and non-opioid autoanalgesia induced by exposure to footshock [53], and clonidine potentiates cold-water swim analgesia [36], which was discussed previously in terms of non-opioid pain inhibition systems. The central loci which are involved in the antinociceptive properties of clonidine appear to be of spinal and supraspinal origin [ 188,233]. This view is reinforced by studies showing that the hypoalgesia induced by blockade of noradrenergic projections to the nucleus raphe magnus can be reversed by blockade of either noradrenergic or serotonergic projections to the spinal cord [112, 113, 216]. Whether the same or similar central loci are associated with the cardiovascular properties of clonidine is not known. The recent observation that both a-adrenoreceptors and opioid receptors coexist in many brain regions and on the same cell suggests that the same central loci could potentially be involved in the pharmacological effects of both a-adrenoreceptor and opioid receptor agonists [3,248]. The outcomes of electrophysiological studies also support the view that cardiovascular systems interact with pain regulatory systems. Ammons, Blair, and Foreman [10,11] have shown that stimulation of the vagal nerve trunk attenuates firing of sympathetic afferents from the heart, which apparently convey information relating to ischemic heart pain. Stimulation of vago-afferent nerves also attenuates the firing of spinothalamic neurons projecting from laminae I, IV, V and VII of the spinal dorsal horn [ 10, l t]. Interestingly, Gahery and Vigier [95] reported that stimulation of vago-afferent nerves produces a diminution of the efficacy of synaptic transmission of somatic afferents in the cunneate nucleus of chloralosed cats. This structure receives primary somesthetic afferents from the dorsal columns of the cord, and more important seems to receive projections from the carotid sinus, but not the aortic depressor nerves. Electrical stimulation of the external cunneate nucleus also induces a bradycardia in cats. Similarly, stimulation of vagai afferent systems impairs transmission in the thoracic and cervical spinoreticular tracts [242]. Cardiopulmonary and sinoaortic baroreceptor input may also modulate transmission at various pontine and medullary structures including nucleus reticularis gigantocellularis, locus coeruleus, NTS, and nucleus raphe magnus. Somatic and visceral input from spinothalamic, spinoreticular, and spinocervical tracts traverse these regions, thus providing the requisite anatomical substrate for the modulation of poorly localized cutaneous sensory information (pain and temperature) as well as highly defined sensory information (touch and pressure). Many of the neuroanatomical substrates associated with central cardiovascular regulation have also been implicated in subserving the analgesia induced by opioids, clonidine, and SPA. Many of these areas contain high concentrations of opioid receptors and peptides [13, 14, 15, 77, 120, 195]. One such structure is the nucleus tractus solitarii (NTS), an elongated nucleus that extends the entire length of the medulla oblongata and receives visceronsensroy input from cranial

C A R D I O V A S C U A L R AND PAIN I N T E R A C T I O N nerves V, VII, IX, and X. Baroreceptor afferents from the carotid sinuses and cardiopulmonary regions project to an area dorsal to the solitary tract and to the medial solitary and commissural nuclei of the NTS [ 156,189]. The NTS contains opiate receptors [13,14] which may function in cardiovascular and somatosensory modulation., As noted previously, analogous to the peripheral activation of the carotid sinus baroreceptors, endorphinomimetic substances injected into the NTS generally lower blood pressure and heart rate, although the opposite outcome is obtained with Dala-2-MetS-enkephalin. The former cardiovascular effects are abolished by apioid receptor blockade [84, 90, 143, 145, 147]. Some of these agents, e.g., morphine and fentanyl, may act to facilitate the input and transmission of baroreceptor afferent impulses within the NTS. The NTS also appears to modulate nociceptive input since microinjection of morphine in this region of the rat is associated with a naloxone reversible analgesia [186], although it should be noted that relatively large doses of morphine were used and the possibility of diffusion to other sites must be considered. The B3 region of Dahlstrrm and Fuxe [69,70] is composed of the nucleus raphe magnus (NRM) and the nucleus paragigantocellularis (NPGC in rat) or the nucleus reticularis magnocellularis (NMC in the cat). This region of the brainstem, as noted earlier, supports many forms of analgesia and receives nociceptive input [88,98]. The NRM has also been implicated in cardiovascular regulation, since stimulation of the rostral or lateral areas of the B3 region induces a pressor response while a depressor response is observed following stimulation of the caudal or medial portions of the B3 [2,271]. In addition, this area participates in the baroreceptor reflex control of blood pressure [118,126] and the modulation of sympathetic nervous system activity [43,66]. Finally, direct enkephalin and substance P projections from the NTS have been revealed by double labeling techniques [21]. Although some controversy exists as to whether the NRM and NPGC represent the same functional unit [17, 18, 98,258] both components project to dorsal horn laminae I-III, and V-VII of Rexed [13, 14, 88, 121,204] and to the thoracic and lumbar interomediolateral cell columns of the spinal cord [17, 43, 121, 157]. The nucleus reticularis gigantocellularis (NRG) is thought to receive a direct projection from the NTS, since nerve terminal degeneration has been observed in the NRG following placement of a small lesion in the medial part of the NTS [ 189]. The NRG projects to the intermediolateral cell column of the cord [118, 189] and to areas of the ventral horn associated with motor control [17,18]. The NRG has been reported to project to the lateral aspects of laminae V of Rexed in the dorsal horn [194]. However, in another study [18] this projection was not observed. The NRG may be able to alter somatosensory and autonomic processes via the NRM since the NRG sends projections to the NRM [96] some of which are enkephalinergic [21]. This region of the brainstem receives nociceptive input [98] and has been implicated in both opioid and non-opioid forms of analgesia. It is also an area which will produce cardio-inhibition [51, 52, 58, 98, 140, 176, 177, 210]. For instance, electrical stimulation or microinjection of morphine in this area produces profound antinociception in response to oro-facial thermal stimulation, suppression of dental tooth pulp evoked field potentials in the subnucleus oralis of the spinal trigeminal complex, suppression of the jaw-opening reflex, and decreases in arterial blood pressure and heart rate [51, 140, 210]. The parabrachial nucleus (PN), which is thought to play a

347 role in the regulation of adrenocorticotrophin (ACTH) release [256] and the defense reaction [65], receives afferent input from the NTS [156, 157, 180, 205]. Efferents, some of which contain enkephalin, project from the PN to the NRM [21,157]. Recent neuroanatomical studies also support a role of the PN in the concomitant modulation of somatosensory and cardiovascular dynamics. Retrograde horseradish peroxidase tracing studies have demonstrated that the PN region sends projections through the spinal cord via the dorsolateral funiculus and ventrolateral funiculus. In addition, anterograde tracing studies have revealed direct spinal projections to the dorsal horn and to autonomic and somatic cell groups [18,121]. In the cat, microinjection of the muscarinic receptor agonist carbachol in the PN induces an analgesia [116, 130, 131]. Various neuroanatomical [205, 220, 239] and electrophysiological [44] studies have demonstrated a direct projection from the caudal portion of the medial solitary nucleus to the paraventricular nucleus (PVN) of the hypothalamus. This region of the neuroaxis plays a major role in homeostatic regulation by modulating neuroendocrine, autonomic, and behavioral responses to environmental stimuli [239]. Efferents from the PVN project to the anterior and posterior hypothalamus as well as to various autonomic centers in the brainstem and spinal cord [239]. In addition, the PVN may modulate somatosensory input at the level of the dorsal horns since direct oxytocinergic projections to laminae I and II have been identified [239]. The nucleus locus coeruleus (LC) is the principle source of noradrenergic neurons in the neuroaxis [12,102] and receives afferent input from the NTS [61,215]. It is a small region, but the LC projects to all levels of the neuroaxis and modulates autonomic, humoral, and somatosensory events. Direct neuronal projections to laminae I-II, IV, VI, and X of the dorsal spinal gray and to various autonomic centers in the spinal cord and brainstem of many species have been demonstrated [165,260, 261]. Functionally, the LC has been implicated in the regulation of somatosensory input and may play a role in the expression of morphine-induced analgesia [137, 196, 218]. In addition, the LC may attenuate the neural, humoral and behavioral responses to environmental stressors [7]. The arcuate nucleus (AN) of the hypothalamus has been shown receiving a direct neural projection from the caudal portion of the medial NTS [205]. This region of the hypothalamus contains the cell bodies of the majority of the opiomelanotropinergic (/3-endorphin and melanocyte stimulating hormone) neurons in the brain (see [181] for review). This region has been reported to support morphineinduced analgesia and electrolytic lesions of the AN region also produces hyperalgesia [27, 128, 193,253, 173]. A variety of behavioral data also provide additional evidence that endogenous pain regulatory systems are linked to cardiovascular systems. Rats with experimental renal hypertension [203,272, 274], desoxycorticosterone (DOCA) acetate hypertension [272], and genetic hypertension [163,203, 214, 272, 274] manifest hypoalgetic behaviors in hot-plate, tail-withdrawal, and paw-pinch assays of pain sensitivity. The only exception to these outcomes was reported by Sitsen and DeJong [230] who found that DOCA-salt hypertensive rats did not manifest hypoalgesia when tested on a 54° degree hot-plate, while genetically hypertensive rats did. However, in our laboratory DOCA-salt hypertensive rats manifest hypoalgesia when tested on a 51 degree hot-plate, suggesting that the negative outcome reported above reflects

348 a "floor effect" due to testing with an extremely hot surface temperature. In each of these forms of hypertension, the hypoalgesia is abolished by prior administration of naloxone, thereby implicating mediation by endogenous opioids. This latter view is also supported by reports that genetic and renal hypertensive rats have elevated levels of opioid activity in the cervical region of the spinal cord [274]. Perhaps of greater significance, the hypoalgesia manifested by SHRs compared to W K Y s is abolished in a time-dependent manner following resection of the right vagal nerve trunk [163], but not following resection of the carotid sinus and aortic depressor nerves [73,200]. These findings suggest that alterations in the low pressure cardiopulmonary baroreceptor reflex arc may subserve the hypoalgesia observed to thermal stimulation in SHRs and also tie into endogenous opioid pain inhibition systems. Genetically hypertensive rats also show less autotomy and stress-related pain following unilateral sciatic nerve sectioning [259]. In accord with the above observations, young and adult humans with essential hypertension show higher sensory and pain thresholds than agematched normotensives in response to electrical stimulation of tooth-pulp [273]. However, the reduction in pain sensitivity to thermal stimulation manifested by rats with these various forms of hypertension is not indicative of a generalized reduction in pain sensitivity to all types of stimuli. SHRs manifest lower detection and pain thresholds than age-matched W K Y s in flinch-jump assays of responsivity to an electric shock stimulus [200]. Moreover, bilateral sinoaortic deafferentation further reduces detection and pain thresholds in both SHRs and WKYs [200]. These outcomes suggest that alterations in the high pressure sinoaortic baroreceptor reflex arc modulate pain sensitivity only to certain forms of noxious stimulation. In accord with this view, SHRs acquire a discrete trial lever press avoidance and wheel-turn avoidance response to an electric shock stimulus at a faster rate than W K Y s [45,237]. Similarly, SHRs acquire conditioned suppression of instrumental responding for food reward to a conditioned stimulus paired with an electric shock stimulus at a significantly faster rate that W K Y s [203]. Finally, acute phenylephrine-induced hypertension attenuates wheel-turn escape/avoidance responding evoked by aversive trigeminal stimulation, and this effect is mediated by activation of the sinoaortic baroreceptor reflex arc since bilateral sinoaortic deafferentation reverses the deficit [76]. Collectively, these findings suggest that activation of the high pressure baroreceptor reflex arc may inhibit pain to certain fe,~wns of noxious stimulation, and that reductions in activity of this arc brought about by resection or resetting of this arc in SHRs augments pain sensitivity. Thus, studies of hypertensive rats indicate a generalized alteration of pain sensitivity, but this is reflected as either a hypoalgesia or a hyperalgesia depending upon the type of noxious stimulation. The above discussions do not represent an exhaustive review of all the possible or known factors and interactions involved in the concomitant modulation of cardiovascular and somatosensory dynamics. Instead, they serve to point out that such an interaction is possible on the basis of existing pharmacological, electrophysiological, neuroanatomical, and behavioral data. Moreover, they also point out the complexity of such an interaction. Future studies should focus on the extent to which somatosensory and cardiovascular dynamics interact at various levels of the neuroaxis. Since many of the neuroanatomical loci discussed above appear to be either directly or indirectly involved in the mod-

RANDICH AND MAIXNER ulation of many physiological functions, it is not unreasonable to assume that the local neuronal circuitry is complex. One possibility is that a single neuron may receive and encode afferent information from both somatosensory and cardiovascular systems (convergence) and project to both the dorsal horn and to spinal autonomic centers. The activation of such a neuron (or population of neurons) by either cardiovascular or somatosensory input may result in the concomitant modulation of both somatosensory input and cardiovascular hemodynamics. In contrast, this same region of the neuroaxis may also contain neurons which selectively encode either cardiovascular or somatosensory information, but each neuron is capable of altering somatosensory input and cardiovascular dynamics at various levels of the neuroaxis. Such a heterogeneous organization, although complex, would provide the organism with a host of somatosensory and visceral responses to physiologically and/or behaviorally relevant stimuli. The degree to which various neural circuits are engaged will be dependent upon the behavioral and physiological relevance of various stimuli. A strongly aversive stimulus may result in stimulation of a subpopulation of neurons in a given area which project to both autonomic and somatosensory areas of the spinal cord. This type of circuitry would prepare the organism to freeze. flee, or fight. In contrast, an individual running a marathon race may use a different subpopulation of neurons within the same neuroanatomical substrate to regulate the various cardiovascular dynamics associated with exercise. From a teleological perspective, such a heterogenous organization would allow an organism a tremendous range of responses to various environmental stimuli.

BARORECEPTOR REFLEX ARC MODULATIONOF PAIN REGULATORY SYSTEMS: A WORKING HYPOTHESIS The findings presented in the preceding sections primarily provide indirect evidence that systems involved with cardiovascular regulation are physiologically linked to endogenous pain regulatory systems. On the basis of these studies, we adopted two working hypotheses which provided the basis for the following experimental manipulations. Clearly, aspects of these proposals will require modification with future research, and they serve primarily as means of establishing some anchor point for research. First, activation of a sub-population of vagal afferents, whose receptors are located in the heart and lungs, and, in part, comprise the afferent limb of the cardiopulmonary reflex arc, should induce antinociception to certain forms of noxious stimulation. Therefore, physiological activation of these receptors by volume expansion, pharmacological activation of these receptors by administration of agents such as the veratrum alkaloids or nicotine, or electrical stimulation of the vagal nerve trunk should all induce analgesia. Conversely, resection of the vagal nerve trunk should be effective in eliminating the analgesia induced by any of the above treatments. Second, stimulation of carotid sinus and aortic depressor afferents whose receptors are located in the carotid sinuses and aortic arch, and comprise the sinoaortic baroreceptor reflex, should induce analgesia to certain forms of noxious stimulation. Physiological activation of these receptors brought about the increases in arterial blood pressure or electrical stimulation of either the carotid sinus or aortic depressor nerve would be expected to induce analgesia. Resection of the sinoaortic baroreceptor reflex arc should be

C A R D I O V A S C U L A R A N D PAIN I N T E R A C T I O N effective in eliminating analgesia induced by any of the above treatments. Before proceeding to experiments which address these proposals, it is necessary to consider both evidence presented previously which seems inconsistent with these proposals and possible limitations in interpreting the following experiments. Malxner et al. [163] reported that the hypoalgesia manifested by SHRs in the hot-plate assay of pain sensitivity was eliminated in a time-dependent fashion following resection of the right vagal nerve trunk and was not affected following bilateral sinoaortic deafferentation. The latter outcome was confirmed by Randich [200]. These findings suggest that changes in low pressure rather than high pressure baroreceptors are important for the hypoalgesia manifested to painful thermal stimulation in SHRs, and when considered in terms of the working hypothesis advanced above, the SHRs should show greater tonic or stress-induced activation of vagal afferents. It has been established, however, that low pressure cardiopulmonary baroreceptors are reset in the SHR, i.e., the threshold of these baroreceptors are reset to a higher level than in W K Y s [40, 206, 243,244], although no quantitative data are available for the rat on gain changes or the sensitivity of these baroreceptors as measured by the slope of the linear portion of the steady-state impulse frequency-pressure curve. This resetting phenomenon would seem at odds with the above proposals. However, the threshold resetting in the SHR is compensated for by decreased venous and left atrial distensability resulting in increased left atrial pressure. These changes in distensability, therefore, will promote a greater increase in the activity of vagal afferents for any given change in pressure in SHRs compared to W K Y s [206]. This view is supported by the findings of Thor6n's group [206, 243,244] showing that inhibition of sympathetic renal nerve activity is significantly greater in SHRs compared to W K Y s for a given increase in plasma volume. Thus, due to these complex changes in venous and atrial distensability, the resetting phenomenon is functionally negated and cardiopulmonary baroreceptors are more sensitive to changes in blood volume in SHRs compared to WKYs. This interpretation is consistent with both the data on vagal influences on antinociception in SHRs and the working hypothesis advanced in the present paper. Similarly, the hyperalgesia manifested by SHRs to shock stimuli in flinch-jump assays of pain sensitivity seems at odds with the view that elevations in arterial blood pressure and activation of the sinoaortic baroreceptor reflex arc inhibits pain. However, in SHRs the sinoaortic baroreceptors are also reset, i.e., they show both a higher threshold for activation and a reduction in their gain. Since the threshold resetting is matched by an increase in baseline arterial pressure, it is possible that the reduction in gain of the arc promotes less activity for any given pressure increase resulting in an overall less sensitive reflex arc compared to the WKY. This account, although highly speculative, would then be parsimonius with both the flinch-jump data obtained in intact animals and data obtained following bilateral sinoaortic deafferentation. However, it is also possible that the augmented responses observed in the SHR in flinch-jump assays resulted from some sensation other than pain. Electrical stimuli activate many different types of cutaneous receptors and peripheral afferents (Aft, AS, C), thereby allowing for the possibility that this behavior was not a function of alterations in nociception per se. Finally, in the following experimental tests of the role of the sinoaortic baroreceptor reflex arc in nociception, a vas-

349 ocohstrictor is used to elevate arterial blood pressure and activate this reflex arc. It is important to note that this is an experimental manipulation which is not indicative of the way an organism might normally raise pressure. Specifically, under normal circumstances we elevate pressure by increasing sympathetic outflow. This is problematic, since under some circumstances, (e.g., increases in sympathetic outflow brought about by fear or anxiety) the input of the baroreceptor reflex arc appears to be overridden at limbic and hypothalamic levels of the CNS, i.e., central clamping of the reflex arc. This points to the difficulties in studying a system in isolation [91, 92, 119], and at the present time we can only acknowledge that certain limits of interpretation are necessary until more information is established about the role of baroreceptor information under such circumstances. EXPERIMENTALTESTS OF BARORECEPTORMEDIATEDCHANGES IN NOCICEPTION The following series of experiments are provided as an initial attempt to test the usefulness of the two proposals regarding baroreceptor mediated changes in nociception advanced in the preceding section. The first series of experiments assessed the view that activation of cardiopulmonary baroreceptors induces antinociception. In the following experiments we have elected to use the term antinociception rather than analgesia. The majority of these data were obtained with the tail-flick assay. At the temperature we used, the tail flick response is a spinally mediated reflex [105, 127]. However, the response is modulated by various supraspinal structures which are able to alter afferent sensory information and/or efferent motor activity. Many of the supraspinal structures discussed previously send projections to areas of the spinal cord involved in somatosensory processing and somatomotor control. In this regard, it may be a gross oversimplification to assume that an elevated tail-flick response latency is indicative of "analgesia." In the first experiment [162], normotensive SpragueDawley rats were implanted with a left-carotid artery catheter for measurement of arterial blood pressure and heart rate, and a right external jugular vein catheter for measurement both of central venous pressure and administration of the volume expander Ficoll (5% in saline). Twenty-four hrs after surgery, each rat was placed in a Plexiglas restraining tube for testing of pain sensitivity to radiant heat applied to the tail (tail-flick assay). Baseline cardiovascular and tail-flick responses were obtained first. Ficoll was then infused for a 2-min period at a rate of 1.97 ml/min. At this point, the Ficoll infusion was stopped and a tail-flick trial administered in conjunction with concurrent measurements of cardiovascular parameters. The infusion was then restarted for another 2-min period, and this procedure continued until a 10-sec tail flick latency was obtained. A 10-sec latency is defined as maximal antinociceptive activity in our laboratory and has been supported elsewhere [148]. The intent of this infusion procedure was to produce graded increases in central venous pressure and determine whether increases in tail-flick latencies tracked the pressure increases. Once a 10-sec latency had been achieved, the infusion procedure was terminated and tail-flick trials were administered every 3 min for the following 27 min to determine the duration of analgesia. Finally, three treatment groups were incorporated into this experiment. Unless otherwise stated, all groups in this experiment and the following experiments contain a minimum of five rats. Group sham-operated served as the primary experimental group to test the view that antinociception was

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associated with increases in central venous pressure. Group vagotomy had received resection of the right vagal nerve trunk four weeks prior to the experiment and served to test whether the efficacy of the volume expansion procedure in altering pain sensitivity depended upon the integrity of vagal afferents. It is important to note that only a right vagotomy was performed since rats do not survive bilateral vagotomy on a long-term basis. Thus, if activation of vagal afferents mediate the change in pain sensitivity, then it should be possible to observe an attenuation of antinociception in right vagotomized rats. A four week recovery period was used to allow for functional deafferentation to occur since the right vagotomy was performed caudal to the nodose ganglion. Finally, a group of sham-operated rats received 20 mg/kg of naltrexone (IP) 10 min prior to testing to determine whether any antinociception observed was due to vagal-induced activation of an endogenous opioid system. The mean pre-infusion baseline tail-flick latencies for groups sham, vagotomy, and naltrexone were 2.11_+0.30, 2.90_+0.28, and 2.76_+0.27 sec, respectively. Figure 1 shows that all treatment groups demonstrated profound increases in tail-flick latencies that persisted across the 27 rain observation period. This was supported by an A N O V A indicating a significant treatment effect, F(2,149)=8.65. Individual differences were determined by Duncan's multiple range test and indicated that the tail-flick latencies of groups shamoperated and naltrexone did not significantly differ at any point across this time period, but group right vagotomy showed significantly shorter tail-flick latencies compared to the other t w o groups during the same time period. Thus, volume expansion does induce antinociception as assayed by the tail-flick reflex and this antinociception is attenuated by resection of the right vagal nerve trunk. These data indicate

that activation of cardiopulmonary baroreceptors, whose afferents travel in the vagi, contributed to this change in pain sensitivity. Naltrexone was without effect suggesting the possibility of mediation by non-opioid pain inhibition system, although the difficulties of opioid receptor antagonist studies have been discussed previously. Scatterplots of the tail-flick indices (i.e., (test trial latency - baseline latency/maximal analgesia (10 s e c ) - baseline latency)) are presented as a function of mean volume/g body weight of Ficoll infused (Fig. 2), mean central venous pressure (Fig. 3), mean arterial pressure (Fig. 4), and mean heart rate (Fig. 5), respectively for the various treatment groups. Linear regression lines and correlation coefficients are presented for descriptive purposes only. Figure 2 shows strong positive correlations between the amount of infusate and increases in tail-flick indices for all treatments. The volume required to induce antinociception is similar to that required to activate vagal afferents and inhibit sympathetic renal nerve activity [206]. However, it is important to note that diuresis was not controlled for in this experiment, thereby contributing variability to these functions. Figure 3 indicates that strong positive correlations existed in groups sham and naltrexone for the magnitude of tail-flick indices and mean central venous pressure, but no significant correlation was observed for the group with right vagotomies. These outcomes are consistent with finding that only right vagotomy attenuated the antinociception induced by volume expansion. Finally, Figures 4 and 5 indicate that mean heart rate and mean arterial blood pressure decreased as a function of the volume expansion procedure and were correlated with increases in tail-flick indices. The hypotension and bradycardia resulting from volume expansion are characteristic of activating the Bezold-Jarisch reflex [243].

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More importantly, these cardiovascular changes provide additional evidence that the volume expansion procedure was effective in activating the cardiopulmonary baroreceptors.

A second means of activating vagal afferents is through the administration of either veratrum alkaloids or nicotine. The veratrum alkaloids are known to engage the BezoldJarisch reflex, primarily by activating chemo-sensitive receptors in the posterior left ventricle. In the following experiment (conducted by P. Hanger and A. Randich), normotensive rats were catheterized with right external jugular vein and left common carotid artery cannulae as described in the

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This figure shows that both 50/~g/kg and 100 ~g/kg of veratrine induced profound antinociception that persisted across a 3-min observation period, whereas 5/~g/kg did not appear different from baseline control values established with saline. These impressions were confirmed with an A N O V A indicating significant effects for drug dose, F(3,12)=46.08 and test trial time, F(3,12)=4.03. Scheffe post-hoe analyses confirmed that only the tail-flick indices of the two larger doses of veratrine differed significantly from saline tail-flick indices at all test trial time points. The middle panel of Fig. 6 shows that arterial blood pressure decreased as a function of this treatment. An A N O V A of arterial blood

pressures indicated a significant effect of drug dose, F(3,12)=8.86 and test trial time, F(4,16)= 11.20. In general, Scheffe post-hoe analyses revealed that only the two larger doses resulted in significant hypotension compared to saline. The bottom panel of Fig. 6 shows that the two larger doses of veratrine also elicited large decreases in heart rate with the "peak" value representing the largest decrease observed during the time period prior to the 15 second trial. These decreases in heart rate were probably a consequence of direct activation of peripheral chemoreceptors, since they occurred within 1-2 seconds of the veratrine infusion. These views were confirmed by an A N O V A of heart rates indicat-

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ing significant effects of drug dose, F(3,12)= 11.39; test trial time, F(4,16)=23.01; and the drug dose X test trial time interaction, F(12,48)=6.18. Scheffe post-hoc analyses indicated that heart rates elicited by the (1) 100 tzg/kg dose differed significantly from saline at peak, 0.25-, 1-, and 3-min values, (2) 50 p.g/kg dose differed from saline at the peak value. On the following day, a similar procedure was used in the same animals except that the rats were infused with equal volumes of saline, 500 /zg/kg naloxone, and 100 /xg/kg of veratrine, in sequence. This procedure was implemented to determine if (1) naloxone alone had any effect on pain sensitivity and cardiovascular function, and (2) naloxone would block the antinociception and cardiovascular changes produced by veratrine. This dose of naloxone completely reverses the analgesia induced by peripheral IV administration of enkephalinamide in our laboratory. Figure 7 presents these data. This figure indicates that naloxone did not affect tail-flick responses when administered alone and did not alter either the antinociception or the cardiovascular changes evoked by infusion of 100/zg/kg of veratrine. These views were confirmed by an A N O V A of tall-flick indices indicating a significant effect of type of drug, F(2,8)=86.75. Scheffe post-hoc analyses revealed that the 100/zg/kg veratrine condition differed significantly from saline which in turn did not differ from naloxone. An A N O V A on arterial blood pressures revealed a significant effect of drug type, F(2,8)=5.06 and test trial time, F(4,16)=7.12. Scheffe post-hoc analyses revealed that 100/xg/kg of veratrine significantly lowered blood pressure compared to saline, which in turn did not differ from naloxone. Similarly, an A N O V A on heart rates indicated a significant effect of drug type, F(2,8)=27.46; test trial time, F(4,16)=9.45; and the type of drug X test trial time interaction, F(8,32)=3.34. Scheffe post-hoc analyses at each time point indicated that saline did not significantly differ from naloxone, but both of these conditions differed significantly from 100/zg/kg of veratrine at all test trial time points. Thus, administration of veratrine induces antinociception, bradycardia, and hypotension. None of these changes appear to involve mediation by endogenous opioids. It should also be recalled that the latter two responses are characteristic of the Bezold-Jarisch reflex and similar to the cardiovascular changes obtained with the volume expansion procedure reported earlier. Recent evidence from our laboratory indicates that the antinociception induced by this veratrine infusion procedure is unaffected by either a right or left vagotomy alone, but is completely abolished in the acute, lightly anesthetized, bilaterally vagotomized rat. These data confirm that veratrine induces antinociception by activating vagal afferents. Finally, in a preliminary study (conducted by C. Hartunian and A. Randich), we have shown that electrical activation of right vagal afferents in the conscious rat induces inhibition of the tail-flick reflex. Rats were implanted with (1) a left arterial catheter for recording of blood pressure and heart rate, (2) an insulated silastic cuff containing silver electrodes around the right vagal nerve trunk, and (3) a ligature around the distal portion of the right vagal nerve trunk caudal to the stimulating cuff. Twenty-four hours later, the rat was placed in the restraining tube in the conscious state. The distal portion of the right vagus was resected by means of the exteriorized ligature. Cardiovascular function was then permitted to stabilize for approximately 15 minutes. Baseline measure were then obtained for tail-flick responses.

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Finally, we stimulated the right vagal nerve trunk for 3 minute epochs recording tail-flick responses and cardiovascular parameters at 15 seconds, l minute, 2 minutes, and 3 minutes after the start of stimulation. Frequency (1.5 Hz, 3.0 Hz, and 6 Hz) and intensity (5 V, 7.5 V, 10 V, and 15 V) were factorially combined for each 3 minute period of stimulation and duration of stimulation was held constant at 0.5 milliseconds. Notice that by resecting the distal portion of the right vagus, all behavioral and cardiovascular changes are a consequence of vagal afferent input to the CNS. Figure 8 presents data from an exemplary rat in this experiment. In general, this figure reveals frequency and voltage dependent changes in antinociception and reflex bradycardia. In summary, physiological (volume expansion), pharmacological (veratrine), and electrical activation of vagal afferents induces antinociception in the rat. These converging operations provide strong support for the view that cardiovascular input to the CNS modifies systems subserving nociception. In our initial experiments examining the view that activation of the sinoaortic baroreceptor reflex arc induces antinociception, Randich and Hartunian [201] showed that continuous intravenous infusion of phenylephrine elevated arterial blood pressure and resulted in a profound antinociception that persisted during a 28-min observation period following termination of the infusion. Further, we were unable to induce antinociception with this continuous infusion procedure in rats which previously had received bilateral sinoaortic deafferentation. Thus, the pressure stimulus must have acted on the sinoaortic baroreceptors to produce the antinociception and did not reflect either a central or non-specific effect of phenylephrine. The continuous phenylephrine infusion procedure was used to parallel the volume expansion experiment described previously, but it was difficult to maintain stable cardiovascular function in a conscious restrained rat under this protocol. Thus, the bolus administration procedure reported previously in the veratrine experiments was adopted in the hope that an extremely brief rise in arterial pressure resulting from a bolus injection of phenylephrine would evoke a small, but reliable reduction in pain sensitivity to radiant heat. In our first bolus injection experiment, rats with external jugular vein and carotid artery catheters received bolus injections of equal volumes of saline, 31.25/xg/kg, 62.5/xg/kg, or 125/xg/kg of phenylephrine. Figure 9 shows the behavioral and cardiovascular changes resulting from this manipulation. This figure shows that only the 62.5 and 125/xg/kg doses of phenylephrine resulted in the production of antinociception. In the 125 tzg/kg condition, maximal antinociception occurs at the 15 second time point, but this is not always found, and in other experiments the antinociceptive function was relatively fiat across all time points. These impressions of the antinociceptive actions of phenylephrine were supported by an A N O V A indicating a significant effect of drug dose, F(3,12)=4.92. In this experiment and all of the following experiments using phenylephrine, a set of contrasts were selected post-hoc using the following procedure: Sample means were analyzed using the method recommended by Rodger [208,209]. F o r each set of means, decisions were made, post hoc, for H = J - I mutually orthogonal contrasts of the form Yjcju)=0. The observed variance ratio for each sample contrast (Fh) was compared with Rodger's critical F values, FlEck]; vl, v2 [208]. The null was rejected if Fh~>F[Ec~]; vl, v2; otherwise, the null was accepted. Using these critical F values, Rodger's method insures that the

355

CARDIOVASCULAR AND PAIN I N T E R A C T I O N

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C A R D I O V A S C U L A R A N D PAIN I N T E R A C T I O N expected proportion of null rejections when all nulls are true will be Ect=.05. Given specified alternatives null contrasts, the decisions for H = J - I mutually orthogonal contrasts implies values for the population means ([209] eqn. 23). The implied population means (expressed in unknown E units) state in an unambiguous fashion the differences, or lack thereof, claimed between values for the various conditions. It is the ordering of these implied means that are presented in the text. In the present experiment, the ordering of implied population mean tail-flick indices across all test trial time points was saline = 31.25< 62.5 < 125. All three doses resulted in substantial and short-lived elevations in arterial blood pressure in terms of a peak response (the maximal response prior to the first tail-flick trial at 15 seconds), and only the two higher doses maintained elevations in pressure at the time of the first tail-flick trials. These views were confirmed by an A N O V A indicating significant effects for drug dose, F(3,12)=22.73; time, F(4,16)=49.44; and the drug dose × time interaction, F(12,48)= 11.83. A set of mutually orthogonal contrasts based upon significant follow-up A N O V A s for main effects at the various time points implied the following ordering of population mean arterial blood pressures at the .25 time point; saline < 31.25 = 62.50 < 125. Finally, all three treatment doses resulted in bradycardia which persisted across the 3 minute observation period relative to saline control values. This was confirmed by an A N O V A indicating significant effects for drug dose, F(3,12)=20.78; time, F(4,16)=38.91; and the drug dose × time interaction, F(12.48) = 15.13. Sets of mutually orthogonal contrast s based upon significant follow-up A N O V A s at the various test trial time points indicated the following orderings of population mean heart rates; at the .25 min time point, saline > 31.25 > 62.5 > 125, and at the 1-, 2-, and 3-min time points, saline > 31.25 = 62.5 > 125. On the following day, the same rats received administration of 500/xg/kg IV of naloxone prior to administration of each of the saline or phenylephrine doses. Once again, phenylephrine resulted in significant antinociception as shown in Fig. 10, and within-subject statistical comparisons revealed that the magnitude of the antinociception was greater under the influence of naloxone than with phenylephrine alone, F(1,4) = 13.70. It is unclear at the present time whether enhancement of antinociception was a true effect of naloxone, since this outcome may also simply reflect repeated days of treatment with phenylephrine for which we did not control. However, we saw no enhancement in the magnitude of antinociception with the repeated days test procedure with veratrine, and at a minimum it indicates that naloxone does not attenuate or eliminate the analgesia. Moreover, the possibility that naloxone potentiates antinociception has parallels in other analgesic systems [133]. Finally, the magnitude of both the arterial blood pressure increases and the reflex heart rate decreases under the influence of naloxone did not significantly differ from those obtained in the absence of the drug. We then examined the effects of administration of 10 mg/kg of phentolamine, an al- and a2-adrenergic receptor blocker, on the antinociception induced by administration of 125/.tg/kg of phenylephrine. Figure 11 presents the results of this manipulation and shows that alpha blockade completely prevented the normal pressor response to phenylephrine and an A N O V A indicated no significant differences in tail-flick indices, heart rates, changes, or blood pressure changes between saline and phenylephrine conditions.

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358 In order to assess whether peripheral or central muscarinic cholinergic receptor mechanisms involved in the production of reflex bradycardia in response to arterial pressure elevations also contributed to the antinociception, either 500 /xg/kg of methyl atropine or 1 mg/kg of atropine sulfate was infused prior to administration of the various doses of phenylephrine described above. Unlike the preceding experiment in which naloxone was administered prior to each dose of phenylephrine, only a single dose of atropine was given at the start of the experiment. Figure 12 shows the outcomes of the atropine sulphate manipulation involving muscarinic cholinergic receptor blockade. Virtually identical results were obtained with the administration of the peripherally acting muscarinic cholinergic blocker, methyl atropine. In general, all rats still showed antinociception to phenylephrine administration, and under both drug conditions the reflex bradycardia was virtually eliminated, indicating a primary role of vagal efferents in mediating the bradycardic response to phenylephrine. Moreover, the low dose of phenylephrine (31.25/zg/kg) was effective in the induction of antinociception with muscarinic receptor blockade by either methyl atropine or atropine sulfate. Presumably, this reflects the larger elevations in arterial blood pressure produced under muscarinic cholinergic receptor blockade of the reflex bradycardia. These views were supported by an A N O V A indicating under the influence of muscarinic receptor blockade, phenylephrine induced significant elevations in tail-flick indices as a function of drug dose, F(4,28)=5.85. Follow-up comparisons indicated the following ordering of population mean tail-flick indices; saline=atropine sulphate < 31.25 < 62.5 < 125 across all test trial time points. Thus, in summary of our preliminary work with phenylephrine we have established that the (1) antinociception is due to phenylephrine induced activation of alpha adrenoreceptors, (2) cholinergic mediated reflex bradycardia is not critical for the antinociception, and (3) opioid receptor antagonists may enhance rather than attenuate the antinociception. This latter findings is of particular significance since the administration of naloxazone, an opioid receptor antagonist, potentiates the analgesia induced by cold-water swim while reducing the analgesia induced by morphine [133]. These potentiation effects have been interpreted as evidence for collateral inhibition between opioid and non-opioid pain-inhibitory systems. Subsequent analyses also indicate that this antinociceptive response does not occur following phenylephrine administration in rats with D L F lesions at the level of C5-C6. These latter findings in conjunction with the data presented earlier suggest some interesting possibilities. Cell bodies originating in the nucleus raphe magnus and lateral reticular nucleus send descending fibers through the dorsolateral funiculus to terminate near preganglionic sympathetic neurons in the intermediolateral horn of the spinal cord. Serotonergic fibers originate in the nucleus raphe obscurus and noradrenergic fibers originate in ventrolateral portion of the lateral reticular nucleus to exert inhibitory effects on preganglionic sympathetic neurons [66,67]. Noradrenergic fibers also originating in the lateral and ventrolateral aspects of the lateral reticular nucleus exert an excitatory effect on preganglionic sympathetic neurons. It is possible, therefore, that these cardiovascular systems may also subserve the antinociception induced by either vagal or carotid sinus activation. The descending serotonergic projection from nucleus raphe obscurus to spinal cord is particu-

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C A R D I O V A S C U L A R A N D PAIN I N T E R A C T I O N larly attractive, since this nucleus has been implicated in both morphine-induced analgesia and SPA. Thus, it is possible that input at the level of the NTS from vagal and carotid sinus afferents is directly projected to the nucleus raphe obscurus (or possibly the lateral reticular nucleus) to effect both withdrawal of sympathetic tone through inhibition of preganglionic sympathetic neurons in the intermediolateral cell columns and inhibition of nociceptive input from receptive fields in the tail. THEORETICAL CONSIDERATIONS:DISEASES OF ADAPTATION AND STRESS-INDUCED HYPERTENSION In the preceding sections, evidence was presented suggesting that endogenous opioid and non-opioid systems regulate the perception of pain. Further, exposure to either unconditioned or conditioned aversive stimuli are known to inhibit pain by activating these systems. Finally, pharmacological, electrophysiological, neuroanatomical, and behavioral data, in conjunction with experiments from our laboratory were presented indicating that cardiovascular systems interact with pain systems. Preliminary analyses suggest that at least under some conditions activation of either sinoaortic or cardiopulmonary baroreceptor reflex arcs induces antinociception in the rat as assayed by the tail-flick reflex to radiant heat. In the present view, the network formed by cardiovascular and pain regulatory systems should participate in the elaboration of adaptive responses to either acute or chronic physical and psychological demands made upon the body; a stress-mechanism vital for organismic survival. As such, we would expect it to exert an influence in situations involving the application of aversive environmental stimuli, and also to be subject to both the laws of conditioning and cognitive factors. Finally, this network may participate in diseases of adaptation. The following sections elaborate on these issues and discusses possible implications of such a position for the etiology of essential hypertension in humans. We would expect the proposed cardiovascular-pain regulatory interactions to be governed by the laws of conditioning, thereby markedly expanding their sphere of influence. In a paradigmatic classical aversive conditioning situation, an organism is presented with an originally neutral environmental stimulus (CS) that is paired with an aversive unconditioned stimulus (US). After repeated pairings of these two events, the CS comes to elicit a conditioned response (CR) which often bears similarity to the unconditioned response (UR) evoked by the US. The acquisition of a classically conditioned response is viewed as an adaptive behavior of the organism to a biologically significant event, i.e., the US [190]. As noted previously, analgesia can occur both as an UR to a US, and as a CR to stimuli associated with aversive USs [55, 56, 57]. The general notion suggested by the present analysis is that (1) unconditioned increases in either arterial blood pressure or central venous pressure following exposure to an aversive US, and/or (2) conditioned increases in either arterial or central venous blood pressure evoked by a CS associated with an aversive US, could potentially contribute to the analgesia via the proposed baroreceptor reflex arc mechanisms. From a teleological perspective, unconditioned analgesia resulting from exposure to an aversive US would be expected to influence the behavior of an organism for a period of time subsequent to US presentation [211], and to be possibly related to such phenomena as reactive inhibition [125] or opponent-process aftereffects [202,232]. To this extent, Maixner and Randich [162] showed that resection of

359 the right vagal nerve trunk attenuated the analgesia resulting from exposure to 30 min of electric footshock, as assessed with both tail-flick and hot-plate assays of pain sensitivity. The conditioned effects would be expected to influence the behavior of an organism during the time of CS presentation, and also serve to reduce the impact of the following aversive US [80, 81, 132]. Conditioned analgesia may be related to such phenomena as conditioned diminution of the UR [132] and the US preexposure effect [202]. In paradigmatic instrumental aversive conditioning situations, the delivery or omission of an aversive US is made contingent upon the emission of a specified response by an organism. In an argument similar to the one advanced in the present paper, Dworkin et al. [76] suggested that blood pressure increases may be instrumentally learned in aversive conditioning situations because they promote a reduction in the aversiveness of the following US through negative reinforcement of the response. Their data demonstrating sinoaortic baroreceptor reflex arc modulation of escape/ avoidance responding in the rat to aversive trigeminal stimulation supports this view. In a similar sense, somatic responses may be acquired in such situations because they activate the proposed baroreceptor reflex arc mechanisms. It remains an open issue whether an organism either is capable of learning to increase blood pressure directly, i.e, instrumental control of autonomic reflexes, or secondarily induces blood pressure increases through somatic activity, e.g, postural adjustments, but according to the proposed model, either change could potentially serve an adaptive function by inhibiting pain. If one accepts the viability of these notions, then interactions between cardiovascular and pain regulatory systems and control by associated conditioning processes may play a key role in diseases of adaptation. The following sections consider this view in light of stress and the development of essential hypertension in humans. F o r many years, investigators have argued that psychogenic and psychosocial stressors contribute to the onset of essential hypertension in humans. Correlative data derived from epidemiological studies and experimental evidence from acute stress studies provide support for this view. A greater incidence of hypertension is observed in migratory populations or populations displaced to a novel environment [225]. Immigrants with greater degrees of social interactions, as judged by the number of ethnic affiliations and memberships, show elevations in blood pressure [20]. Populations which are placed in stressful environments also tend to demonstrate elevated arterial blood pressure [226]. The incidence of hypertension has been reported to increase following natural disasters [213], in populations victimized by war [101,172], and in combat troops stationed in aversive situations [101]. Transient hypertension has been observed in medical school students during exams [264] and in individuals engaged in emotional conversations [104, 250]. In short, these studies are highly suggestive that "environmental stress" contributes to the development of hypertension, although this is not to deny other important predisposing factors. Animal studies also indicate that physical and psychological stressors contribute to the onset and maintenance of hypertension. Subjecting rats to various forms of noxious stimulation induces a rapid and sometimes persistent hypertension [39, 41, 42, 11 l, 122, 191,231]. Interestingly, many of these studies used stressors which were described in the aforementioned studies of stress-induced analgesia. For

360

RANDICH AND MAIXNER

example, electric shock [107,108] and immobilization stress [142] have been shown to both induce hypertension in the SHR. Similarly, various shock contingencies have been used as an effective laboratory model of inducing hypertension in rodents and primates. These include the classical and instrumental conditioning procedures described earlier [39,226]. The results of these studies indicate that conditioned forms of hypertension do represent a useful model of human essential hypertension to the extent that (1) during the initial phase of conditioning, the blood pressure is elevated as a result of increased cardiac output, as occurs during the labile phase of essential hypertension, (2) as conditioning progresses the blood pressure remains elevated as a consequence of increase peripheral vascular resistance, as occurs during essential hypertension, and (3) the hypertension induced by conditioning is maintained by both sympathetic adrenergic and non-adrenergic influences [39]. The interpretation of these studies is that application of environmental stressors, which initially promotes acute transient hypertension, may well eventuate into a more chronic hypertension if the stress could be maintained for longer periods of time. Studies using genetically hypertensive rats also support the hypothesis that psychogenic and/or psychosocial factors contribute to the development of chronic forms of hypertension [93]. Studies have shown that higher brain centers involved with the expression of emotionality contribute to hypertension in these animals [182, 183, 269, 270]. SHRs manifest greater aggressiveness, alerting responses, and defensive reactions to novel stimuli than W K Y s [169, 170, 183, 207]. Moreover, the neuroendocrine and neurochemical profile of the SHR is similar to that of an animal under stress, and to the human with essential hypertension [110,183]. SHRs have increased circulating ACTH, TSH, and thyroxine [93]. SHRs also manifest exaggerated sympathetic responses to both acute and chronic forms of stress [111,269]. Recent studies have found the SHRs raised in conditions that diminish environmental input (social or light deprivation) show attenuation of the development of hypertension, once again suggesting that environmental stressors play some role in hypertension [109, 111, 141]. Pharmacological studies indirectly support the view that psychogenic stressors contribute to the development of hypertension. Drugs with antihypertensive properties also tend to reduce stress. F o r example, the benzodiazepines are known to both reduce pressor responses and tachycardia induced by posterior hypothalamic stimulation [50, 60] and antagonize the cardiovascular responses associated with the defense reaction evoked by stimulation of the perifornical region of the lateral hypothalamus [60]. These regions of the brain have also been associated with autonomic nervous system expression of emotions. Propanolol and clonidine, drugs widely used as antihypertensive agents, also produce sedation [60,246]. Clonidine has also been shown to diminish the hypertensive response of the cat when confronted with a dog by increasing the gain of the baroreceptor reflexes [246]. Finally, microinjection of cionidine into the anterior hypothalamic preoptic region of the rat and cat also results in

activation of the carotid sinus baroreceptor reflex [60,2361. Based upon the observations that both acute and possibly chronic forms of hypertension can be induced by a wide variety of natural and experimental aversive environmental stimuli, and that various antistress agents also possess antihypertensive properties, it can be argued that hypertension is in part a disease of adaptation [223]. In light of the view advanced in the present thesis, however, we question the commonly held position that acute and even chronic forms of hypertension necessarily represent a failure of adaptive mechanisms. In contrast, the present view purports that hypertension, at least in the acute form, may provide some form of psychophysiological relief in the face of environmental stressors. Specifically, inhibition of pain and/or associated motivation-affective changes brought about by elevations in blood pressure may service the organism by reducing stress associated with aversive environmental stimulation. Conditioning mechanisms may then be engaged, and in the future, the organism may instrumentally evoke elevations in arterial blood pressure or show Pavlovian conditioned increases in arterial blood pressure in anticipation of environmental stress. Thus, this view considers that essential hypertension in the human may reflect the long-term detrimental effects of an organism that has engaged short-term coping responses to stressors. Admittedly, such a coping mechanism would have to be engaged for extended periods of time to contribute the development of hypertension, but all the evidence suggests that the time course of development for hypertension is long and that the types of stressors which contribute to the development of hypertension are of a chronic, pervasive nature. This view also implies that elevations in blood pressure are reinforcing. Recent reports of opioid induced facilitation of brain reward systems [158, 185,234,235,241] provide support for this view, although the precise interface remains to be determined since opioid involvement in reward and analgesic properties have been dissociated (1) behaviorally [168], (2) with respect to tolerance [78], and (3) with respect to the effectiveness of opiate receptor antagonists in altering responding maintained by intracranial self-stimulation of various brain loci [22, 78, 249]. It should be recalled that the experimental research presented in the present paper obtained no evidence of opioid involvement in cardiovascular induced changes in pain sensitivity. None-the-less, we feel these preliminary experiments and reports of cardiovascular induced changes in pain sensitivity warrant serious consideration as a possible mechanism underlying organismic adaptation to stressors, and possibly the development of essential hypertension in humans.

ACKNOWLEDGEMENTS This project was supported by a grant from N.I.H. to A. Randich (MSI8341). We would like to thank Drs. R. F. Kirby and R. T. Ross for their comments on an earlier draft of this manuscript.

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