Integrated activity of cardiovascular and pain regulatory systems: Role in adaptive behavioural responses

Progress in NeurobiologyVol. 40, pp. 631 to 644, 1993 Printed in Great Britain. All rights reserved

0301-0082/93/$24.00 © 1993Pergamon Press Ltd

INTEGRATED ACTIVITY OF CARDIOVASCULAR A N D PAIN REGULATORY SYSTEMS: ROLE IN ADAPTIVE BEHAVIOURAL RESPONSES T. A. L ow cg Department of Physiology, The Medical School, Birmingham B I 5 2TT, U.K. (Received 7 April 1992)

CONTENTS 1. Centrally-mediated analgesia as part of an integrated behavioural response 2. Central pain control systems 2.1. The dorsolateral and lateral PAG 2.1.1. Behavioural responses 2.1.2. Autonomic changes 2.1.3. Analgesia 2.1.4. Efferent pathways 2.1.5. Interactions with other systems 2.1.6. Functional significance 2.2, The ventrolateral periaqueductal grey matter 2.2.1. Behaviour 2.2.2. Autonomic changes 2.2.3. Antinociception 2.2.4. Descending efferent pathways 2.2.5. Interactions with other systems 2.2.6. Functional significance 2.3. Nucleus tractus solitarius 2.3.1. Behaviour 2.3.2. Autonomic changes 2.3.3. Antinociception 2.3.4. Central pathways 2.3.5, Interactions with other systems 2.3.6. Functional significance 3. Concluding remarks Acknowledgements References 1. CENTRALLY-MEDIATED ANALGESIA AS PART O F AN INTEGRATED BEHAVIOURAL RESPONSE Responsiveness to sensory stimulation can undergo marked changes during the daily life cycle. The sleeping or drowsy person may not respond to auditory or tactile stimuli which would be sufficiently intense to evoke orienting or arousal responses in the alert individual. In contrast, a highly aroused individual may be unresponsive to nociceptive stimuli which would evoke sensations of pain in the alert subject and certainly arouse the sleeper. In relation to perception of pain, there are many dramatic and commonly experienced examples of altered sensory responsiveness. Injuries sustained during competitive sport often fail to evoke sensations or responses characteristic of pain at the time they arc inflicted. Fleeing from danger, panic and fighting arc all bcbavioural states in which sensory stimuli that cause actual physical injury evoke neither bcbavioural reactions nor conscious perception of pain at the time they arc inflicted. The phenomenon of 'endogenous analgesia' was initially documented more than four decades

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ago by Botcher (1946) in his now classic studies on the absence of pain in men wounded in battle. It is perhaps surprising then, that given the enormous therapeutic potential of being able to harness an endogenous pain control system, it is only in the past two decades that significant progress has been made towards understanding the physiological basis of this form of analgesia. The initial search for a neurophysiological basis of 'endogenous analgesia' was given considerable impetus by three important findings. The 'gate theory' of pain (Melzack and Wall, 1965) was the first to propose a neuronal network in which the rcsponsivencss of the central nervous system to a particular sensory input could be determined, not only by the physical properties of a stimulus impinging on it, but also by other internal and external influences acting on the nervous system at the same time. In the simplest form of this model it was proposed that interactions between large and small affercnt fibre inputs to the dorsal horn of the spinal cord could produce a reduction in responsiveness to input from peripheral nociceptors. Of equal importance, the model also rcw,ognised that, in addition to control at

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the segmental level, there must be descending central influences on spinal processing of noxious input. These descending influences, which could be controlled by changes in behavioural status, would set the level of activity of the spinal gate. Shortly after the publication of the 'gate theory', a neuroanatomical substrate for the central component of the pain control pathway was provided in the now classic paper by Reynolds (1969) who reported that surgical analgesia could be produced in the rat by electrical stimulation in the midbrain periaqueductal grey matter (PAG). Within the next few years, a third breakthrough: the identification of endogenous opioids and opiate receptors (Pert and Snyder, 1973; Hughes et aL, 1975) provided a pharmacological basis for the existence of 'natural' or endogenous pain control mechanisms within the central nervous system. These fundamental advances in neurophysiological and pharmacological knowledge paved the way for a period of intense activity in the field of pain research. At the present time, more than a score of brain sites have been identified at which electrical stimulation can produce antinociception. The presence of so many pain control systems is in itself a puzzle. It is possible that the many pain control systems work in parallel, serving as back-up systems for each other. However, this seems unlikely, particularly in the light of recent neurophysiological analysis of the mechanisms and pathways that mediate the analgesia which can be evoked from these different sites. In almost every case, inhibitory modulation of peripheral nociceptor input to the spinal and trigeminal dorsal horns has been found to make a major contribution to the antinociception. Moreover, studies of the descending efferent pathways to the spinal cord from different 'pain control' areas have revealed that at the level of the midbrain and medulla there is a convergence on to a relatively small number of final common pathways to the spinal cord. Another factor emerging is that the functional properties of the antinociception evoked from different brain sites is not always the same. Thus the quality of the sensory loss, in terms of somatotopic localisation, selectivity for sensory modality, afferent fibre type etc. may be an important feature which characterises the analgesia produced by activation of the individual 'pain control' systems of the brain. In other words, although there appear to be many different pain control regions, each may have access to only one of a small number of common neuronal cores which serve as effector systems that mediate a particular quality of hypoalgesia. The reductionist approach to endogenous analgesia outlined above has yielded much valuable information regarding the physiology and pharmacology of the pathways which can mediate antinociception. In terms of understanding the physiological relevance of the various pain control systems, the approach has been less profitable. Significant progress towards this end has, however, been achieved by taking a more holistic view which considers other changes in bodily function and behaviour patterns which occur at the same time as the antinociception. When this approach is taken it becomes clear that stimulation in certain 'pain control' areas produces a complex re-

sponse of which antinociception is but one component. Indeed, the 'side effects' of activating pain control pathways, often considered an impediment which hindered the study of antinociception, may actually provide important clues to the functional role of this phenomenon. By taking a multidisciplinary approach, in which autonomic, motor and behavioural changes are considered in addition to the modulation of somatosensory responsiveness, endogenous antinociception comes to be viewed as part of an integrated response of the whole animal which may be an adaptive reaction that is triggered by a particular set of environmental stimuli. In this article, three pain control regions within the brain (the dorsolateral/lateral PAG, the ventrolateral PAG and nucleus tractus solitarius (NTS)) have been chosen for analysis in the context of the behavioural, somatomotor and autonomic changes that accompany the sensory loss which can be evoked by activation of neurones in these structures. When analysed in this way, it becomes clear that antinociception elicited by stimulation of the dorsal and ventral systems in the PAG is produced largely by activating two independent but interactive core pain control systems which are located respectively in the ventrolateral and ventromedial medulla. These two systems appear to be activated under different environmental conditions and produce antinociception which is an integral component of two fundamental adaptive responses of the whole animal. In contrast, analgesia evoked from NTS does not appear to be part of this type of integrated adaptive response and may be independent of the bodily changes which are also controlled by this structure. Indeed, it is even possible that the analgesia evoked from NTS may be an adjunct which is secondary to activation of the dorsal PAG control system, and mediated by activation of the core control pathway which is utilised by the ventrolateral PAG system (see Sections 2.3.4-2.3.6).

2. CENTRAL PAIN CONTROL SYSTEMS 2.1. Ti-m DORSOLATERALAND LATERALPAG 2.1.1. Behavioural responses

In the conscious or unanaesthetised decerebrate animal, stimulation in the dorsolateral and lateral sectors of the PAG produces dramatic species specific behavioural responses which are characteristic of flight or defence behaviour (Bandler, 1982; Depautis et al., 1989; Kiser and Lebovitz, 1975; Kiser et ai., 1978; Sehutz et al., 1985). In the cat, for example, discrete microinjections of an excitatory amino acid into the pretentorial region of the PAG, to selectively activate neuronal cell bodies, evoked displays of threatening behaviour which included vocalisation, flattening of the ears, arching of the back and an increase in extensor muscle tone (Bandler and Carrive, 1988). Further caudally, in the suhtentorial region, stimulation evoked a 'flight' response charaeterised by running and jumping and attempts to escape the experimental cage (Zhang et aL, 1990). Studies in the rat have emphasised a similar rostrocaudal organisation. Thus the dorsolateral/lateral

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PAG appears to be subdivided into a rostral defensive zone and a caudal avoidance zone (Bandler and Depaulis, 1991). The behaviour patterns which can be evoked by stimulation of the dorsolateral/lateral PAG, particularly the 'explosive' escape reactions which occur in response to electrical stimulation in the caudal zone, have led several investigators to consider this region of the PAG as an 'aversive' area (Fardin et al., 1984; Prado and Roberts, 1985). This view reinforces the results obtained in earlier conditioning studies in which it was found that rats would readily learn to bar press in order to terminate, or obtain a reduction in the intensity of, a stimulus applied to the dorsolateral/lateral PAG (Kiser and Lebovitz, 1978; Schmitt et al., 1974). These behavioural signs of fear or aversive emotional states in animals are supported by the reports of subjective sensations which can be evoked by stimulation in the dorsal PAG in man. Patients described unpleasant feelings of fear, anxiety, agitation and impending doom (Nashold et al., 1969; Young, 1989). Indeed, the presence of such sensations has effectively precluded use of stimulation in the dorsal PAG for pain relief in the clinical situation. 2.1.2. Autonomic changes

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evoked by stimulation in the dorsolateral/lateral PAG (Mayer et al., 1971). Typically, as stimulation currents were increased progressively from subthreshold levels, the analgesia appeared suddenly and concurrently with the appearance of aversive motor reactions (Fardin et al., 1984; Prado and Roberts, 1985). Indeed, in those studies it was not usually possible to separate the antinociception from the affective behavioural response and this observation prompted the authors to consider whether the analgesia may be an indirect effect which is secondary to the stress of the stimulation. The presence of motor responses has also placed serious constraints on the study of analgesia evoked from dorsal stimulation sites. However, by suppressing the emotional and motor components of the response with general anaesthetics, it has been possible to study the characteristics of the antinoeiception under more controlled conditions. As a result, it is now recognised that stimulation in the dorsolateral and lateral sectors of the PAG can exert a descending inhibitory influence on transmission of sensory information through the dorsal horn which is selective for noxious inputs in that input from A and C fibres is suppressed, whilst activity relayed by low threshold cutaneous afferent fibres remains unchanged (Duggan and Morton, 1983). Interestingly, recent evidence from studies in conscious animals now suggests that responsiveness to tactile sensory input, particularly from the head region, may even be enhanced by activation of neurones in the dorsolateral/lateral PAG (Bandler and Depaulis, 1991). A further characteristic of analgesia evoked from the dorsolateral/lateral part of the PAG is the presence of cardiovascular changes. The antinociception evoked from this region was always accompanied by a defensive pattern of cardiovascular and autonomic change (Duggan and Morton, 1983; Lovick, 1985b; see Section 2.1.2). Thus a raised cardiac output was diverted to skeletal muscle at the expense of the circulation to the skin and viscera.

The dorsolateral PAG is recognised as an important area for autonomic control, particularly in relation to cardiovascular function. Electrical or chemical stimulation in the dorsal quadrant of the PAG produces a distinctive pattern of cardiovascular change which characteristically includes an increase in arterial blood pressure and heart rate with vasoconstriction in renal, mesenteric and cutaneous vascular beds but vasodilatation in skeletal muscle (Abrahams et al., 1960; Yardley and Hilton, 1987; Duggan and Morton, 1983; Lovick, 1985b; Hilton and Redfern, 1986; Carrive et al., 1987). This pattern of cardiovascular change is accompanied by an increase in the rate and depth of respiration and reinforced by release of catecholamines from the 2.1.4. Efferent pathways adrenal medulla (Stoddard-Apter et al., 1983; Yardley and Hilton, 1987). In addition, other autoThe dorsolateral/lateral PAG sends excitatory pronomic signs of arousal are present such as piloerec- jections to spinally-projecting cells in nucleus paration, pupillary dilatation and retraction of the gigantocellularis lateralis of the rostral ventrolateral nictitating membrane (cats) or widening of the palpe- medulla (RVLM) (Andrezik et al., 1981; Li and bral fissure and exophthalmus (rats). In the conscious Lovick, 1985a; Lovick et al., 1984; Van Bockstaele et or unanaesthetised decebrate animal, the autonomic aL, 1991). Both the analgesia and the cardiovascular and cardiovascular changes occur concomitantly with components of the response could be attenuated by the behavioural signs of aggression or defence de- lesions of the RVLM or by local application of scribed above (see Section 2.1.1). Evidence from inhibitory amino acids to block neuronal transstudies in man also suggests a linkage between con- mission in this region (Hilton et al., 1983; Lovick, trol of behavioural state and cardiovascular changes 1985b; Foong and Duggan, 1986). The RVLM conby the dorsal PAG. In human patients who were tains functional pools of sensory and motor control receiving electrode implants for relief of intractable neurones as well as a population of sympathocxcitapain, the aversive sensations evoked from the dorsal tory neurones which determine the level of activity in PAG were accompanied by a pressor response with the spinal sympathetic outflows to different vascular tachycardia (R.F. Young, personal communication). beds (Lovick, 1987; Dampney and McAllen, 1988; Lovick and Li, 1989). The axons of the medullospinal cells descend in the dorsolateral funicuhis to 2.1.3. Analgesia terminate in the dorsal and ventral horns of the Studies of changes in sensory responsiveness spinal cord and in the intermediolateral cell column evoked from the PAG in conscious animals have (Locwy and McKellar, 1981; Locwy et al., 1981). established that a profound antinociception can be Activation of the cell bodies in the RVLM evokes JPN 40/~---H

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antinociception accompanied by cardiovascular changes (Gray and Dostrovsky, 1985; Lovick, 1986; Sidall and Dampney, 1989) and an increase in the excitability of somatic motoneurones (Lovick and Li, 1989). Thus the programme for the characteristic patterning of sympathetic and somatomotor activity which originates in the dorsolateral/lateral PAG during defensive/attack behaviour is imposed on the relevant control neurones in the RVLM in order to generate the integrated pattern of response which underlies defensive behaviour. Interestingly, both the descending sympathoexcitatory and antinociceptive systems in the RVLM appear to be tonically active (at least under some forms of anaesthesia). Thus in addition to mediating the cardiovascular changes and analgesia associated with defensive behaviour, they appear to make a major contribution to the level of tonic descending inhibition which is present on spinal reflexes (Hall et al., 1982; Wall, 1967) as well as determining the basal level of sympathetic vasomotor activity. 2.1.5. Interactions with other systems

In addition to the dorsolateral/lateral PAG, a number of other regions of the brain have been implicated in the expression of aversive emotional behaviour in conscious animals. Evidence is accumulating to suggest that these systems may be functionally and anatomically linked to the dorsolateral/lateral PAG system and so share the same common ventrolateral effector system in the medulla. The perifornical 'defence area' of the ventral hypothalamus has long been associated with cardiovascular responses related to emotional behaviour. Electrical stimulation in this region produces rage or attack behaviour which is accompanied by the 'defence' pattern of cardiovascular change (Abrahams et al., 1960; Mancia et aL, 1972; Mancia and Zanchetti, 1981). The cardiovascular defence response evoked from this region was always accompanied by inhibition of noxious sensory input to the spinal dorsal horn (Morton and Duggan, 1986). Thus the whole pattern of response evoked from the ventromedial part of the hypothalamus is identical to that which is integrated by the dorsal PAG. These results must, however, be viewed with caution for there is evidence that the defence region in the hypothalamus may not be as extensive as indicated by the results of studies using electrical stimulation techniques. At many sites microinjection of an excitatory amino acid into the hypothalamic 'defence area', to selectively stimulate cell bodies, failed to reproduce the effects of electrical stimulation (Hilton and Redfern, 1986), However, in more recent studies it has been possible to localise a group of cells within a restricted region of the rostral anterior hypothalamus/preoptie area (AHA/POA) which can evoke the whole pattern of the cardiovascular defence response with accompanying antinociception (Unger et aL, 1988; Itoi et aL, 1991; Lovick and Lumb, 1991). Cells in the rostral AHA/POA send projections to the PAG which terminate preferentially in the dorsolateral sector

(Beitz, 1982; Semanenko and Lumb, 1992). Moreover, lesions of the dorsolateral/lateral PAG have been shown to attenuate analgesia evoked from the hypothalamus (Aimone et al., 1988). Thus the efferent pathway which mediates the integrated hypothalamic 'defence response' may utilise the dorsolateral PAG/RVLM pathway to the spinal cord (Fig. 1). The amygdala is another region of the brain which is involved in the expression of defensive behaviour. Stimulation in the basolateral and central amygdaloid nuclei can evoke aggression or defensive behaviour in conscious animals together with the characteristic pattern of the cardiovascular defence response (A1 Maskati and Zbrozyna, 1989; Hilton and Zbrozyna, 1963; Timms, 1981). Evidence from microinjection studies indicates that this region is also involved in antinociception although its main role seems to be in the control of the affective or emotional components of the response to noxious stimuli rather than in modulating the pain threshold (Calvino et aL, 1982; Kalivas, 1982; Rogers, 1978). Neurones in the defence area of the amygdala send projections to the dorsolateral/lateral PAG and to the RVLM (Marchand and Hagino, 1983; Takayama et al., 1990; Thompson and Cassell, 1989; Rizvi, 1991; Wallace et al., 1989). Thus it seems likely that both the amygdaloid and hypothalamic defence areas can modulate the activity of the dorsolateral/lateral P A G - R V L M control system in the midbrain (Fig. 1). 2.1.6. Functional significance

The fear and panic sensations which are elicited by stimulation in the dorsolateral and lateral sectors of the PAG in man are echoed by the outward motor and autonomic signs of extreme emotional arousal which characterise the response to stimulation in this region in animals (see Section 2.1.1). The underlying pattern of cardiovascular response which supports this type of behaviour is a fundamental reaction to many forms of novel or threatening, and hence potentially dangerous, stimuli. In its weakest form it can be evoked by mild alerting stimuli, as part of the orienting response (Martin et al., 1976). Thereafter it is present as a component in a continuum of arousal responses which culminate in full blown expressions of rage or defence behaviout (Mancia et al., 1972; Caraffa-Bragga et al., 1973; Vikvn et al., 1991). By diverting the cardiac output to skeletal muscle and restricting perfusion of the viscera, the body becomes primed for motor activity. In the face of a perceived threat, such a process would clearly have an adaptive value by maximising the efficiency of subsequent motor activity during attack or defensive behaviour. The antinociceptive component of the response may similarly be considered to have an adaptive value in emergency situations. Physical insults which lead to stimulation of nociceptors are an integral part of many attacking or defensive behavioural encounters. The presence of pain normally leads to a set of reactions which are designed to promote healing and recovery such as immobility, removal and

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DEFENCE AREA

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Facilitated Movement Adrenomedullary activation

Sympathoexcitation

Sympathoinhibition

Antinociception

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Fxo. 1. Schematic diasram to show some of the major structures and neural pathways which are involved in mediating the antinociception and associated cardiovascular and somatosensory changes which can be evoked by activation of the pain control systems in the ventrolateral PAG, the dorsolateral/htteral PAG and nucleus tractus solitarius.

protection of the affected part etc. However, in the acute emergency situation these types of response would clearly be inappropriate. On the other hand, by suppressing pain during a temporary reduction in

responsiveness to peripheral input from nociceptors, the organism is able to continue with motor behaviour directed towards the more immediate demands associated with survival.

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The ventrolateral sector of the PAG lies ventral to the level of the aqueduct and lateral to the dorsal raphe and oculomotor nuclei. Stimulation in this region evokes changes in behavioural, cardiovascular and somatosensory responsiveness which are readily distinguishable from the patterns of response which can be elicited from the dorsolateral/lateral PAG.

blood pressure and bradycardia (Carnve and Bandler, 1991; Lovick, 1992a). In the rat this hypotensive reaction was always accompanied by vasedilatation in hindlimb muscles (Lovick. 1992a) whereas in the cat, hindlimb muscle vasodilatation was mainly evoked from the rostral half of the ventrolateral PAG whilst vasodilatation in the kidney was the predominant vascular response to stimulation in more caudal regions (Carrive and Bandler, 1991).

2.2.1. Behaviour

2.2.3. Antinociception

Electrical stimulation in the ventral PAG in the rat has been reported to evoke motor effects, particularly rotational movements, during the period of stimulation (Fardin et al., 1984). More recent findings suggest that these movements may be an artifact of the electrical stimulation method, perhaps due to stimulus spread or to activation of fibres of passage, since the effect is not reproduced by selective activation of neuronal perikarya. In conscious, freely moving cats and rats, microinjection of an excitatory amino acid in the subtentorial portion of the ventrolateral PAG produced a reaction termed 'hyporeactive immobility' (Bandler and Depaulis, 1991). This response was characterised by cessation of all locomotion and was often accompanied by a dramatic reduction or a cessation in other forms of spontaneous behaviours together with a decreased responsiveness to external stimuli, such as approach/investigation by a partner or touch of the body. Other studies have shown that stimulation in the caudal ventrolateral PAG, in the region adjacent to the dorsal raphe nucleus, has positively reinforcing properties. For example, there are several reports of self-stimulation behaviour in response to low intensity electrical stimulation in the caudal half of the ventrolateral PAG in the rat (Liebman et al., 1973; Wolfe et al., 1971). Stimulation more rostrally in the ventrolateral PAG evoked signs of aversion in these experiments. The results from the behavioural studies in animals are supported by recent data obtained from clinical experience of stimulating the ventral PAG in man. Human patients describe sensations of 'warmth, floating or generalisecl well-being' at threshold stimulation levels (Young, 1989). Thus in man too, stimulation in the ventrolateral PAG appears to have positively reinforcing or rewarding qualities.

Several properties of the analgesia evoked from the ventrolateral PAG distinguish it from the antinociceptive effects which can be evoked by stimulation in the dorsolateral and lateral sectors. This finding suggests that the quality of the sensory loss evoked from dorsal and ventral stimulating sites in the PAG is not the same. Stimulation in the ventrolateral PAG produces a reduction in responsiveness to noxious stimuli which has been considered 'pure' analgesia by some authors since at threshold intensities of stimulation it appears free from motor side effects or signs of aversion (Mayer et al., 1971; Fardin et al., 1984). Moreover, the analgesia evoked by stimulation at ventrolateral sites has been shown to appear gradually and to be graded with respect to stimulus strength (Fardin et al., 1984). In this respect it shows a marked contrast to the analgesia evoked from stimulating dorsal sites, which appeared suddenly and concurrently with signs of aversion (Fardin et al., 1984). Data from experiments in anaesthetised preparations have shown that at the spinal level, inhibition of sensory input evoked from the ventrolateral sites is non-selective and extends to both A- and C-fibres (Duggan and Morton, 1983). (Tile sensory loss evoked from more dorsal sites was selective for C-fibre input.) Furthermore, there are pharmacological differences between analgesia evoked from dorsal and ventrolateral sites. Microinjection of morphine into the ventrolateral PAG induced analgesia, whereas injection of the opiate into dorsotateral and lateral sites did not (Yaksh et al., 1976; Yeung et al., 1977). Moreover, only the antinociception evoked from ventrolateral sites could be blocked by the opiate antagonist naloxone (Cannon et al., 1982).

2.2. THE VENTROLATERAL PERIAQUEDUCTAL GREY MATTER

2.2.2. Autonomic changes Studies with electrical stimulation have failed to distinguish a clearcut pattern of cardiovascular change in response to stimulation in the ventrolateral PAG (Lovick, 1985b). However, when microinjection of an excitatory amino acid was used to selectively activate neuronal perikarya, stimulation in the ventrolateral PAG produced a characteristic pattern of response which was clearly distinguishable from the 'defence' pattern of sympathoactivation which could be evoked by stimulation at more dorsal sites (see Section 2.1.2). In both the rat and cat, stimulation of ventrolateral neurones produced a fall in

2.2.4. Descending efferent pathways Anatomical and physiological evidence indicates that the autonomic and antinociceptive responses evoked from the ventrolateral PAG are mediated via relays in the medullary raphe nuclei. Neurones in the ventrolateral PAG project extensively to the ventromedial medulla where they make excitatory connections with neurones in nucleus raphe magnus (NRM) and raphe obscurus (NRO) (Beitz et al., 1983; Mason et al., 1985; Lakes and Basbaum, 1988). Neurones in NRM, but not NRO, send projections to the dorsal horn of the spinal cord (Basbaum et al., 1978; Loewy, 1981). Stimulation in NRM has been shown to produce a profound and widespread analgesia which is largely due to inhibition of responsiveness of dorsal horn cells to input from peripheral nociceptors (see Besson and Chaouch, 1987, for review). Lesions of

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NRM were effective in blocking the analgesia evoked by stimulating ventral but not dorsal sites in the FAG (Behebehani and Fields, 1979; Prieto et al., 1983). Thus the weight of evidence indicates that the descending pathway to the dorsal horn, which mediates the analgesia evoked from the ventrolateral PAG, relays through the NRM. The descending pathways which mediate the cardiovascular and motor changes evoked by stimulation in the ventrolateral PAG are less well understood, although there is mounting evidence which points to involvement of the medullary raphe system. Neurones in both NRM and NRO send extensive projections to the intermediolateral cell column (Basbaum et al., 1978; Loewy, 1981 and Holstege, 1991, for review). Stimulation in these medullary raphe nuclei with both electrical and chemical methods evokes both pressor and depressor responses (Dreteler et al., 1991; Futuro-Neto et al., 1990; Jones and Gebhart, 1988; Lai and Siegel, 1990; McCall, 1984; McCall and Humphrey, 1985; Minson et al., 1987). In electrophysiological studies, some midline cells showed properties characteristic of sympathoexcitatory neurones whilst others were sympathoinhibitory (McCall and Clement, 1989). The depressor effects which are evoked by stimulation in the ventrolateral PAG could be due either to a direct excitation of sympathoinhibitory neurones in the raphe or, alternatively, to disinhibition of tonically active sympathoexcitatory cells in the raphe or in the RVLM. Recent experiments have provided data which supports the latter suggestion. In these studies, stimulation in the ventrolateral PAG was found to exert an inhibitory influence on sympathoexcitatory neurones in the RVLM via a relay in NRM and NRO (Lovick, 1992b; Wang and Lovick, 1992). In addition to their projections to autonomic motor control groups in the spinal cord, neurones in NRM and NRO project to somatic motoneurone groups (Holstege, 1991, for recent review). The ventromedial medullary reticular formation has long been known to contain a generalised inhibitory area which affects responsiveness of both flexor and extensor motoneurones (Magoun and Rhines, 1946; Jankowska et al., 1968). Furthermore, in recent experiments in the conscious cat, chemical activation of cells in the rostral ventromedial medulla produced a reduction in muscle tone with a fall in blood pressure (Lai and Siegel, 1990). It is possible therefore that the descending pathway from the ventrolateral PAG engages the inhibitory autonomic and somatomotor control systems in NRM and NRO to produce the whole pattern of antinociception, immobility and sympathoinhibition which characterises the response to stimulation in this part of the midbrain (Fig. 1). 2.2.5. Interactions with other systems Evidence is beginning to accumulate which suggests that there may be considerable interaction between the control systems which originate from the dorsal and ventral parts of the PAG. In particular, recent experiments have shown that neurones in the ventrolateral PAG can modulate activity in the pathway which descends from the dorsolateral/lateral

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PAG. Stimulation in the caudal part of the ventrolateral PAG, at the level of the dorsal raphe nucleus, inhibited the cardiovascular components of the response evoked from the dorsolateral/lateral PAG (Lovick, 1992a). In eleetrophysiological studies, much of this inhibitory effect was found to occur by modulation of activity in the cardiovascular defence pathway at the level of the synaptic relay in the RVLM (Lovick, 1992b). This inhibitory effect was reduced by microinjection of an inhibitory amino acid into NRM and the rostral part of NRO (.Wang and Lovick, 1992). Thus modulation of the cardiovascular defence response from the ventrolateral PAG appears to be mediated indirectly by activation of neurones in the medullary raphe. 2.2.6. Functional significance The integrated pattern of response evoked by stimulation in the ventrolateral PAG exhibits many of the properties of the behavioural state which follows a period of prolonged physical or emotional stress both in man and in animals. In most individuals, there is a need for a period of rest and recuperation following intense mental activity, emotional arousal or prolonged physical exertion. In man, the 'relaxed' behavioural state which follows exercise is often accompanied by a feeling of well-being--the 'joggers high'. Quantitative physiological measures have reported that the elevations in mood which characterise this post-exercise state are accompanied by physiological changes which include sympathoinhibition and a naloxone-sensitive reduction in responsiveness to pain (Shyu et al., 1982; Janal et al., 1984; Floras et al., 1989; Kemppainen et al., 1990). Interestingly this pattern of behaviour is identical to that evoked by stimulation of the ventrolaterai PAG in both human patients and in experimental animals (see Sections 2.1.2 and 2.1.3). At the present time, no direct causal relationship has been demonstrated between exercise-induced sympathoinhibition, hypoalgesia and immobility and the pattern of response which is evoked by activation of the ventrolateral PAG. However, there is an increasing body of indirect evidence from studies in both man and animals which suggest that activation of high threshold afferents from muscle and joints may stimulate the inhibitory control system of the ventrolateral PAG. In experimental animals, prolonged physical exercise or long periods of low frequency stimulation of high threshold afferent fibres from muscle have been found to evoke a long lasting hypoalgesia with sympathoinhibition and immobility (Yao et al., 1982; Hoffmann and Thoren, 1988; Jorum, 1988; Bing et al., 1990; Hoffman et al., 1990a, b, c, d, e). Typically, the response was slow to build up, often taking 10-20 min to develop, but then outlasted the initial stimulation period by several hours. In addition, there was evidence for the involvement of endogenous opioid peptides in mediating all aspects of the response. Interestingly, a similar pattern of response to that induced by exercise or stimulation in the ventrolateral PAG can be evoked by acupuncture stimulation. Traditional acupuncture stimulation is based on manual or electrical stimulation of high threshold

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affercnts from muscles and joints (Liu, 1983). The fully developed acupuncture response is characterised by peripheral warming (vasodilatation), hypoalgesia, physical relaxation and a sense of well-being (Andersson et al., 1973; Omura, 1975; Ernst and Lee, 1986). This pattern of response bears a striking similarity to that reported in human patients after electrical stimulation in the ventrolateral PAG (Young, 1989). Thus acupuncture, by activation of high threshold afferents from muscle, may replicate some of the long term physiological after-effects of strenuous exercise. Investigations into the neurophysiological basis of acupuncture have provided an important link between stimulation of high threshold afferents from muscle and activation of the inhibitory control systems of the ventrolateral PAG. Effective acupuncture has been shown to engage a descending opioid pathway from the arcuate nucleus which activates the ventrolateral PAG-medullary raphe system (Chiang et al., 1979; Huangfu and Li, 1988; Wang et al., 1990). These experiments have highlighted a striking commonality between the type of afferent input to the CNS which is induced by acupuncture or prolonged periods of exercise and the integrated physiological response which is produced by these two forms of stimulation. It seems highly likely that they both engage the ventrolateral PAG control system to mediate their effects. 2.3. NUCLEUS TRACTUSSOLITARIUS 2.3.1. Behaviour Whilst the above discussions have considered analgesia as part of an integrated response of the organism to changes in its external environment, it is possible that there may be a separate control system which initiates similar integrated responses to changes in its internal environment. There are already several indications that intvroceptive stimuli which lead to reflex changes in cardiovascular function may produce antinoeiception. Recent evidence implicates the nucleus tractus solitarius (NTS) in the dorsomedial medulla as the common control region which mediates these effects. NTS acts as the first central relay for a large number of afferents from the heart and vasculature as well as the abdominal viscera. Its pivotal role in the control of blood pressure has long been ~.ognised (see Spyer, 1981, for review) but it is only recently that NTS has been considered important in the control of sensory responsiveness (Lewis et al., 1987). It is possible, then, that NTS could be another region within the brain stem which can control responsiveness to pain and regulate the cardiovascular system.

sponds by initiating a pattern of changes in cardiovascular activity which limits the disturbance in arterial pressure. Essentially, a rise in mean arterial pressure evokes a reflex pattern of response which consists of a decrease in heart rate and peripheral resistance, the latter produced by vasodilatation in the major resistance beds of skeletal muscle and gut (see Spyer, 1981; Shepherd and Mancia, 1986, for reviews). Conversely, when arterial blood pressure falls there is a reduction in ongoing activity in the baroreceptor afferents which leads to an increase in cardiac output mediated by mechanisms which are the opposite of those outlined above. In addition to input from the arterial baroreceptors of the carotid sinus and aortic arch, NTS receives information from low pressure cardiopulmonary vagal afferents concerning pressure changes produced by variations in venous return to the heart or in circulating blood volume. Expansion of plasma volume produces a vagally-mediated fall in blood pressure and heart rate with significant vasodilatation in the renal vascular bed (Rickstein et al., 1979). In contrast to the rapid phasic response of the arterial baroreceptors, the response of the low pressure system is relatively slow. Whilst the initial phase of the response may be a neuronally-mediated renal vasodilatation, the longer term effects on renal-function, which produce a net loss of fluid, are likely due to the actions of circulating hormones such as atrial natriuretic factor, which is released from cardiac myocytes in response to atrial stretch (Anderson et al., 1986; Khraibi et al., 1987; Kohno et al., 1987; Schultz et al., 1988; Thoren et al., 1986; Volpe et al., 1987). 2.3.3. Antinociception Electrical stimulation in NTS in the rat has been shown to produce an antinociception which is opioidmediated (Lewis et al., 1987). In addition, many of the stimuli which activate high and low pressure baroreceptor afferent input to NTS have been shown to be antinoeiceptive. For example, Thurston and Randieh (1990) recently showed that in the rat, an acute increase in arterial blood pressure produced by occlusion of the abdominal aorta evoked a widespread decrease in responsiveness to noxious stimulation of the fore- and hindlimbs and the tail. Acute volume expansion which would stimulate cardiopulmonary vagal afferent input to NTS has also been shown to induce antinoeiception. Other stimuli which can produce a similar vagally-mediated antinociception include direct electrical stimulation of the vagus nerve or intravenous injection of serotonin or stable enkephalin analogues (Maixner and Randich, 1984; Randieh et al., 1987; Meller et al., 1990; Aicher et al., 1991; Maixner et al., 1991).

2.3.2. Autonomic changes Neurones in NTS respond to changes in peripheral cardiovascular status which are relayed by afferents from high and low pressure baroreceptors in the heart and vasculature. Changes in the pattern of firing of high pressure baroreceptor afferents from the carotid sinus and aortic arch signal phasic changes in systemic arterial pressure, such as those associated with postural variations. The central nervous system re-

2.3.4. Central pathways The cardiovascular changes which are initiated by NTS in response to stimulation of high pressure baroreceptors are relayed by multiplepathways to the spinal cord. Although NTS sends projections to the intermediolateral cell column which can influence the sympathetic outflow directly (Spyer, 1~1, for review), there is also evidence that a significant

CARDIOVASC~ARANDPAINP-d~Ut~ON proportion of the reduction in vasomotor tone produced by baroreceptor stimulation is mediated indirectlyby inhibitingthe activityof sympathoexcitatory control neurones in the rostral ventrolateral medulla (Sun and Guyenet, 1985; McCall, 1986). Other pathways which relay in the medullary raphe nuclei may also be involved. Recent studies suggest that the cardiovascular changes which are evoked by vagal afferent stimulation are mediated by similar pathways. Randich et al. (1990) found that the depressor response evoked by electricalstimulationof vagal afferentsrequired the integrityof neurones in nucleus raphe magnus and in the rostral( R V L M ) and caudal ( C V L M ) ventrolateralmedulla (Fig. I). In contrast, antinociceptionevoked by the same vagal stimulation was unaffected by excitotoxiclesions of the ventrolateralmedulla but required the integrityof descending pathways to the spinal cord from the locus coeruleus and N R M (Randich et aL, 1990; Ren et aI., 1990) (Fig. l). At present, the pathway(s) by which N T S mediates the antinociception evoked by stimulation of high pressure baroreceptors is not known. Although these studiesare incomplete, itis already clear that the organisation of the efferentpathways which mediate the antinociception and cardiovascular changes from N T S differsin several ways from those which descend from the PAG. The pathways which mediate the differentcomponents of the response induced by stimulation of vagal afferents appears to diverge at the level of the firstsynaptic relay in NTS. Moreover, more than one pathway appears to be involved in mediating both the antinociception and cardiovascular components of the response. Finally,some of the pathways which mediate responses from N T S utilise neurones in the efferent pathways from both the dorsal and ventral control systems which emanate from the PAG. 2.3.5. Interactions with other systems On both anatomical and functional grounds, it is becoming clear that NTS does not function as an integrated control system in the same manner as the dorsolateral/lateral PAG and the ventrolateral PAG. Indeed, under physiological conditions, vagallyevoked antinociception mediated via NTS may even be secondary to activation of the descending control system in the dorsolateral/lateral PAG (see Section 2.3.6) and mediated by the medullary raphe effector system (see Section 2.3.4). The phasic and tonic adjustments in cardiovascular functioning which are integrated by NTS thus appear to be independent of the analgesia. 2.3.6. Functional significance Two of the major physiological influences on neurones in NTS arise from high and low pressure baroreceptors in the heart and major blood vessels. In the freely moving organism, NTS receives a constantly varying input from sinoaortic baroreceptor afferents due to the changes in gravitational forces on the circulation produced by alterations in posture. The reflex responses evoked in sympathetic and parasympathetic nerves produce changes in the activity of the heart and peripheral vasculature which

639

act to oppose such changes and ensure that arterial pressure is maintained within the limited physiological range which ensures adequate perfusion of vital organs. The physiological role of the antinociception which can be evoked by activation of high pressure baroreceptors is obscure. Indeed, it is not even known whether the phasic changes in baroreeeptor input induced by alterations in posture are adequate to produce antinociception. Even if they are, it is difficult to envisage the significance of such transient changes in somatosensory responsiveness as an animal moves round its environment. Under pathological conditions the chronic elevations in arterial pressure which are present during hypertension might be expected to produce an adequate stimulus for antinociception. However, the 'resetting' of baroreceptors that occurs after prolonged exposure to high arterial pressures (Gonzales et al., 1983) would prevent a sustained increase in input to the CNS from baroreceptor afferents. Indeed, although analgesia has been reported in spontaneously hypertensive rats, it was unaffected by sinoaortic denervation (Maixner et al., 1982). These results suggest that neither transient nor sustained increases in blood pressure are likely to produce analgesia. However, it is possible that the system may be activated by medium term increases in arterial pressure such as those produced during hypertensive episodes associated with fear or defensive type behaviour states (see Section 2.1.1). Thus a barnreceptor-induced antinociception could reinforce the analgesia which is a component of the defence reaction. It is well-established that the cardiopulmonary afferent system plays an important role in the maintenance of body fluid volume. The vagally-mediated changes in cardiovascular function in response to an increase in blood volume increase the capacitance of the vascular system and divert blood to the kidney to facilitate the longer term reductions in body fluid volume. The functional role of cardiopulmonary vagal afferent-induced hypoalgesia in this 'housekeeping system' for body fluid volume is less obvious. However, since the chemosensitive vagal nerve endings may be activated by a variety of blood borne agents (Randich et al., 1987; Meller et al., 1990) the system may be activated under physiological conditions other than changes in plasma volume. One possibility is that it may be stimulated during defensive or stress-induced behaviour. Certain stressors, such as prolonged footshock, have been snown to evoke release of enkephalin-like opioids from the adrenal medulla (Lewis et al., 1982). Adrenomedullary sympatboactivation is also a component part of defensive behavioural and autonomic responses in animals (Stoddard et ai., 1987; Robinson et al., 1983; Yardley and Hilton, 1987). Moreover, circulating opioids have been shown to activate the vagal afferent analgesia system (Randich et ai., 1987). Thus vagal afferent-evoked analgesia secondary to release of endogenous opioid peptides from the adrenal medulla could make a contribution to the antinociception which occurs during defensive or other forms of stress-induced behavioural responses (Fig. 1).

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In contrast to the descending control systems from the PAG, there does not appear to be a particular set of physiological conditions or a specific behavioural state which relates to the antinociception and cardiovascular changes which can be evoked from NTS or by vagal afferent stimulation. Rather, changes in cardiovascular control and antinociception seem to be evoked independently under different circumstances. The dichotomy between the pain control and cardiovascular control systems is further emphasised in pathological states. Several studies have shown that both hypertensive patients and spontaneously hypertensive strains of rat (SHR) are less responsive to pain than normal individuals (Wendell and Bennett, 1981; DeJong et al., 1982; Maixner et al., 1982). In the SHR, the hypoalgesia, but not the hypertension, could be blocked by naloxone or reduced after unilateral vagotomy (Maixner et al., 1982). This suggests that although activation of vagal afferents underlies the analgesia associated with hypertension, there may not be a direct causal relationship between analgesia and hypertension. Indeed, other studies have shown that the hypoalgesia is independent of raised blood pressure in the SHR (de Jong et al., 1982). However, both SHRs and hypertensive patients show a profile of hyperresponsiveness to mental stress which includes a significant increase in plasma levels of adrenaline (Nestel, 1969; McCarty and Kopin, 1978). Since co-release of opioids with catecholamines has been shown to occur during sympathoadrenomedullary activation (Viveros and Wilson, 1983), it is possible that the hypoalgesia which is a feature of certain hypertensive states may be due to adrenomedullary sympathoactivation, evoked as part of an exaggerated response to stress.

3. CONCLUDING REMARKS

By viewing pain control as a component of a broader adaptive response of the whole animal to a particular set of behavioural or physiological stimuli, it has been possible to identify two pain control systems, one of which originates from cells in the dorsolateral and lateral sectors of the PAG and the other from neurones in the ventrolateral PAG. The integrated patterns of response which are initiated by activation of the control systems of the dorsal and ventral PAG have so far been considered as separate entities. In reality it may be more appropriate to view the two systems as inter-related control mechanisms which act synergistically to mediate different phases of a spectrum of adaptive behavioural responses which is constantly changing in order to meet the physiological and environmental challenges posed by life in a potentially hostile environment. As discussed above, threatening stimuli elicit an aggressive or defensive behavioural response which is integrated by activation of the descending pathways from the dorsolateral/lateral PAG. A pattern of physiological changes ensues which facilitates intense physical activity. At the same time, and as a direct consequence of this behavioural response, increased input to the

central nervous system from high threshold muscle afferents during exercise will begin to activate the inhibitory systems of the ventrolateral PAG which favour relaxation (in its broadest sense). The apparent paradox caused by simultaneous activation of two antagonistic physiological control systems, one excitatory and one inhibitory, can be reconciled by viewing the descending systems from the dorsal and ventral PAG in terms of the defensive--recuperative model of behaviour proposed by Bolles and Faneslow (1980). In the early acute phase of an emergency or life-threatening encounter, the rapidly activated defence system in the dorsolateral/lateral PAG will be engaged to counteract the threat and ensure the immediate survival of the organism. If this behavioural strategy is successful in the form of defeat of the opponent or by escape, then the stimulus which originally served to initiate it (e.g. threat, attack by a predator, etc.) will be reduced and hence the defensive behavioural pattern of response will subside. In the meantime, the intense physical activity which occurs when the defensive system is engaged will give rise to a sustained increase in high threshold muscle afferent input to the CNS and initiate activity in the long lasting ventrolateral PAG system. As active defensive behaviour wanes, the activity of the ventrolateral system will begin to predominate, and thus a pattern of recuperative behaviour begins to dominate which enables the animal to recover from the period of stress. In contrast to descending control from the PAG, attempts to analyse the pain control elicited from NTS in the context of accompanying cardiovascular and behavioural changes fail to show the analgesia as part of an adaptive response. Although under experimental conditions it is possible to demonstrate that stimuli which activate high pressure baroreceptor afferents can produce hypoalgesia as well as cardiovascular changes, it is not clear whether such stimuli would be encountered under physiological conditions in daily life. In terms of vagal afferent-induced analgesia, it is possible that subtle changes in responsiveness to noxious input occur as a result of variations in vagal input during circulatory disturbances. However, the analgesia seen in certain hypertensive states has been shown to be independent of the raised blood pressure (de Jong et al., 1982). Furthermore, even if vagally induced antinociception occurs as part of the response to stress (see Section 2.3.6), it is probably a consequence of the adrenomedullary sympathoactivation which results from activation of the defensive system in the dorsolateral/lateral PAG (Fig. 1). In the light of these findings, it may be more appropriate to view NTS as a region which is involved both in the control of the cardiovascular system and in the control of sensory responsiveness. However, the two control systems function independently under different physiological conditions and are not normally activated together as part of an integrated adaptive response of the whole animal. support from the Medical Research Council is gratefully acknowledged.

Acknowledgements--Financial

CARDIOVASCULAR AND PAINREGULATION

REFERENCF~ ABRAHAMS,V. C., HILTON, S. M. and ZBROZYNA,A. W. (1960) Active muscle vasodilatation produced by stimulation of the brainstem: its significance for the defence reaction. J. Physiol., Lond. 154, 491-513. .MetieR, S. A., L~vm, S. J. and RANDICH,A. (1991) Antinociception produced by electrical stimulation of vagal afferents: independence of cervical and subdiaphragmatic branches. Brain Res. 542, 63-70. AIMO~rE, L. D., BAU~X,C. A. and GEmL~,RT, G. F. (1988) Brainstem relays mediating stimulation-produced antinociception from the lateral hypothalamus in the rat. J. Neurophysiol. 8, 2652-2663. AL M~ro~Tl, H. and ZBROZY~A,A. W. (1989) Cardiovascular and motor components of the defence reaction elicited in rats by electrical and chemical stimulation in the amygdala. J. auton, nerv. Sys. 28, 127-132. A m ~ o N , J. V., CmusTOwDr.S, N. D. and BLOOM, S. R. (1986) Plasma release of atrial natriuretic peptide in response to blood volume expansion. J. Endocr. 109, 9-13. Am~EI~SON, S. A., ERICSSON, T., HOLMOI~N, E. and Llm~QlaST, G. (1973) Electroacupuncture. Effect on pain threshold measured with electrical stimulation of teeth. Brain Res. 63, 393-396. Am~ZZK, J. A., ~ - P A ~ V , V. and PALAV,S. L. (1981) The nucleus paragigantocellularis lateralis in the rat: demonstration of afferents by retrograde transport of horseradish peroxidase. Anat. Embryol. 161, 373-390. BArcOtr~, R. (1982) Induction of 'rage' following microinjections of glutamate into midbrain but not hypothalamus of cats. Neurosci. Lett. 30, 491-513. BANDLER, R. and CAR~W, P. (1988) Integrated defence reaction elicited by excitatory amino acid microinjection into the midbrain periaqueductal grey of the unrestrained cat. Brain Res. 439, 55-106. BANDtJ~, R. and DEPAULIS, A. (1991) Midbrain periaqueductal gray control of defensive behavior in the cat and rat. In: The Midbrain Periaqueductal Gray Matter, pp. 175-198. Eds. A. D~PAULISand R. BANDLER.Plenum, New York. BASRALrM,A. I., CLA~rroN,C. H. and F~LDS, H. (1978) Three bulbospinal pathways from the rostral medulla of the cat: an autoradiographic study of pain modulatory systems. J. comp. Neurol. 178, 209-224. E~Cl-n~, H. K. (1946) Pain in men wounded in battle. Ann. Surg. 123, 96-105. BEHEBE~m, M. M. and FIELDS,H. L. (1979) Evidence that an excitatory connection between the periaqueductal gray and nucleus raphe magnus mediates stimulation produced analgesia. Brain Res. 170, 85-03. BEITZ, A. J. (1982) The organisation of afferent projections to the midbrain periaqueductal gray of the rat. Neuroscience 7, 133-159. BEITZ, A. J., MULL~Tr, M. A. and W m ~ , L. L. (1983) The periaqueductal gray projections to the rat spinal trigemihal, raphe magnus, gigantocellularis pars alpha and paragigantocellular nuclei arise from separate neurons. Brain Res. 288, 307-314. BESSON,J. M. and CHAOUC~,A. (1987) Peripheral and spinal mechanisms of nociception. Physiol. Rev. 67, 67-186. BIN~, Z., VmLA~VA, L. and L~ BAGS,D. (1990) Acupuncture and diffuse noxious inhibitory controls: naloxonereversible depression of activity of trigeminal convergent neurones. Neuroscience 37, 809-818. BOLt£S, R. C. and FANSF~OW, M. (1980) A perceptualdefensive-recuperative model of fear and pain. Behavl Brain Sci. 3, 291-323. CALV~NO,B., ~ U ~ , G. and BEsso~, J. M. (1982) Possible involvement of the amygdaloid complex in morphine analgesia as studied by electrolytic lesions in rats. Brain Res. 233, 221-226.

641

CANNON, J. T., PgmTO, J. G. and Lm~srdNV, J. C. 0982) Evidence for opioid and non-opioid forms of stimulationproduced analgesia in the rat. Brain Res. 243, 315-321. CARAFFA-BRAGA,B., GRANTA, L. and IhNOTTX,O. (1973) Changes in blood-flow distribution during acute emotional stress in dogs. Pflugers Arch. 339, 203-216. C~,glW, P. and B,~qVL~, R. (1991) Viscerotopic organisation of neurones subserving hypotensive reactions within the midbrain periaqueductal grey: a correlative functional and anatomical study. Brain Res. 541, 206-215. C~LrVE, P., Di~a, SL~Y, R. A. L. and BANDLEg,R. (1987) Excitation of neurones in a restricted region of the midbrain periaqueductal grey elicits both behavioural and cardiovascular components of the defence reaction in the unanaesthetised decerebrate cat. Neurosci. Lett. 81, 273-278. CmANO, C. Y., Tu, H. C., CHAO, Y. F., P~, H., Ku, H. K., CHENG,J. K., SHAN,H. Y. and YANG,F. Y. (1979) Effects of electrolytic lesions or intracerebrai injections of 5,6-dihydoxytryptamine in raphe nuclei on acupuncture analgesia in rats. Chin. Med. J. 92, 129-136. DA~a'N~Y, R. A. L. and MCALLEN,R. M. (1988) Differential control of sympathetic fibres supplying hindlimb skin and muscle by subretrofacial neurones in the cat. J. Physiol., Lond. 395, 41-56. DEJONG, W., PETTY, M. A. and SITS~q, J. M. A. (1982) Hypoalgesia in spontaneously hypertensive rats (SHR) is not related to blood pressure. Br. J. Pharmac. 77, 438. DEPAULIS,A., BAWLER,R. and V~G~.s, M. (1989) Characterisation of pretentorial periaqueductal gray matter neurons mediating intraspecific defensive behaviours in the rat by microinjections of kalnic acid. Brain Res. 486, 121-132. DRETELER,G. H., WOUTERS,W., SAXENA,P. R. and RAMAGE, A. G. (1991) Pressor efects following microinjection of 5HT~ receptor agonists into the raphe obscurus of the anaesthetised rat. Br. J. Pharmac. 102, 31%322. DUGGAN, A. W. and MORTON,C. R. (1983) Periaqueductal grey stimulation; an association between selective inhibition of dorsal horn neurones and changes in peripheral circulation. Pain 15, 237-248. ERNST,M. and LEE, M. H. M. (1986) Sympathetic effects of manual and electrical acupuncture of the Tsusanli knee point: comparison with the Hoku hand point sympathetic effects. Expl Neurol. 94, 1-10. FAROIN, V., OUVEP,AS, J. L. and BESSON,J. M. (1984) A reinvestigation of the analgesic effects induced by stimulation of the periaqueductal gray matter in the rat. I. The production of behavioural side effects together with analgesia. Brain Res. 306, 105-123. FLORAS,J. S., SLINKEY,C. A., AYWARD,P. E., SEALS,D. R., THOREN, P. N. and MARK, A. L. (1989) Post exercise hypotension and sympathoinhibition in borderline hypertensive men. Hypertension 14, 28-35. FOONG, F. and DUOOAN, A. W. (1986) Brainstem areas tonically inhibiting dorsal horn neurones: studies with microinjection of the GABA analogue piperidine-4-sulphonic acid. Pain 27, 361-371. FUTURO-NETO,H., SILVA,S. R., DA~rrAS,M. A. and GmaEv, M. P. (1990) A comparison of the effects of stimulation within raphe nuclei on arterial pressure in the anaesthetised rabbit and rat. Acta Physiol. Pharmac. Latinoam. 40, 175-184. GONZALES,E. R., KRmGER, A. J. and SAPRU,H. W. (1983) Central resetting of the baroreflex in the spontaneously hypertensive rat. Hypertension 5, 346-352. GRAY, B. G. and DOSTROVSKY,J. O. (1985) Descending inhibitory influences from the periaqueductal gray, nucleus raphe magnus and adjacent reticular formation. I. Effects on lumbar spinal cord nociceptive and nonnociceptive neurons. J. Neurophysiol. 49, 932-947. HALL, J. G., DUGGAN,A. W., MORTON,C. R. and JOHNSON, S. M. (1982) The location of brainstem neurones tonically

642

T.A. LOVlCK

inhibiting dorsal horn neurones in the cat. Brain Res. 244, 215-222. HILTON, S. M., MARSHALL,J. M. and T I ~ s , R. J. (1983) Ventral medullary neurones from defence areas of the eat and their effect on blood pressure. J. Physiol. 345, 149-166. HILTON,S. M. and REVeF.RN,W. S. (1986) A search for brain stem cell groups integrating the defense reaction in the rat. d. Physiol. 378, 213-228. HILTON, S. M. and 7mROZYNA,A. W. (1963) Amygdaloid region for defence reaction and its efferent pathway to the brain stem. d. Physiol., Lond. 165, 160-173. HOI~'MANN,P. and THOKEN,P. (1988) Electric muscle stimulation in the hind leg of the spontaneously hypertensive rat induces a long-lasting fall in blood pressure. Acta physiol, scand. 133, 211-220. HOFFMANN, P., CARLSSON,S., SKAm'HEVlNSSON,J. O. and THOKEN,P. (1990a) Role of different serotonergic receptors in the long-lasting blood pressure depression following muscle stimulation in the spontaneously hypertensive rat. Acta physiol, scand. 139, 305-310. HOFFMANN, P., C~d~LSSON, S. and THOREN, P. (1990b) The effects of/~-, c5- and r-opioid receptor antagonists on the pain threshold increase following muscle stimulation in the rat. Acta physiol, stand. 140, 353-358. HOFFMANN,P., DELLE, M. and THOREN,P. (1990c) Role of opioid receptors in long lasting pressure depression after electrical muscle stimulation of the hind leg of the rat. Acta physiol, scand. 140, 191-198. HO~MANN, P., SKARPm~OINSSON, J. O., DELL, M. and THOREN, P. (1990d) Electrical stimulation of the gastrocnoemius muscle in spontaneously hypertensive rat increases the pain threshold: role of different serotonergic receptors. Acta physiol, stand. 138, 125-132. HOFF~C~NN, P., SKARPHEDINSSON,J. O. and THOKEN, P. (1990e) Electric muscle stimulation in the spontaneously hypertensive rat induces a post-stimulatory reduction in activity: role of different opioid receptors. Acta physiol. scand. 140, 507-514. HOLSTEGE,G. (1991) Descending motor pathways and the spinal motor system: limbic and non-limbic components. Prop. Brain Res. 87, 307-421. HU^NGFU, D. H. and LI, P. (1988) The inhibitory effect of ARC-PAG-NRO system on the ventrolateral medullary neurones in the rabbit. Chin. d. Physiol. Sci. 4, 115-125. HUGHES,J., SmTH, T. W., KOffI'ERLITZ,H. W., FOTHERGILL, L. A., MORGAN,B. A. and MORRm, H. R. (1975) Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature 258, 577-579. ITOl, K., BADUER,E., TSCHOPE,C., CULMALI,J. and UNGER, Y. (1991) Localisation of the substance P-induced cardiovascular responses in the rat hypothalamus. Brain Res. 5f~8, 123-126. JANAL,M. N., COLT, E. W. D., CLARK,W. C. and GLUSMAN, M. (1984) Pain sensitivity, mood and plasma endocrine levels in man following long distance running: effects of naloxone. Pain 19, 13-25. JANKOWSKA,E., LUND,S., LUNDBERG,A. and POMPEIANO,O. (1968) Inhibitory effects evoked through ventral rcticulospinal pathways. Arch. Ital. Biol. 106, 124-140. JONES, S. L. and OESHART,G. F. (1988) Inhibition of spinal nociceptive transmission from the midbrain, pons and medulla in the rat: activation of descending inhibition by morphine, glutamate and electrical stimulation. Brain Res. 460, 281-296. JORUM, E. (1988) The analgesic effect of peripheral nerve stimulation in various tests of nociception. Acta physiol. scand. 133, 131-138. IC~LIVAS,P. W., GAU, B. A., NE~.aOFF, C. B. and PRANGE, A. J. (1982) Antinociception after microinjection of neurotensin into the central amygdaloid nucleus. Brain Res. 243, 279-286.

KEMPPAINEN,P., PAALASMAA,P., PERTOVAARA,A. A. and JOHANSSON,G. (1990) Dexamethasone attenuates exercise-induced analgesia in man. Brain Res. 519, 329-232. KISER, R. S. and LEBOVITZ,R. M. (1975) Monoaminergic mechanisms in aversive brain stimulation. Physiol. Behav. 145, 47-56. KlSER, R., GERMAN,D. C. and LEaOVlTZ,R. M. (1978) Serotonergic reduction of dorsal central gray area stimulationproduced aversion. Pharmac. Biochem. Behav. 9, 27-31. KHRAIBI, A. A., GRANGER,J. P., BURNETT,J. C., WALKER, K. R. and KNOX, F. G. (1987) Role of atrial natriuretic factor in the natriuresis of acute volume expansion. Am. J. Physiol. 252, R921-R924. KOHNO, M., CLEC,G, K. B. and SAMSHI,M. P. (1987) Effects of volume change in circulating immunoreactive atrial natriurctic factor in rats. Hypertension 10, 171-175. LAI, Y. Y. and SIEGEL,J. M. (1990) Cardiovascular and muscle tone changes produced by microinjection of cholinergic and glutaminergic agonists in dorsolateral pons and medial medulla. Brain Res. 414, 27-36. LAKOS,S. and BASBAUM,A. I. (1988) An ultrastructural study of the projection from the midbrain periaqueductal gray to spinally projecting, serotonin-immunoreactive neurons of the medullary nucleus raphe magnus in the rat. Brain Res. 443, 383-388. LEWIS, J. W., TORDO~T, M. G., SHERMAN, J. E. and LmBESKIND,J. C. (1982) Adrenal medullary enkephalinlike peptides may mediate opioid stress analgesia. Science 217, 557-559. LEWIS,J. W., BALDRIGHI,G. and AKIL, H. (1987) A possible interface between autonomic function and pain control: opioid analgesia and the nucleus tractus solitarius. Brain Res. 424, 65-70. LI, P. and LOVlCK,T. A. (1985) Excitatory projections from hypothalamic and midbraln defence areas to nucleus paragigantocellularis lateralis in the rat. Expl Neurol. 89, 543-553. LOEWV, A. D. (1981) Raphe pallidas and raphe obscurus projections to the intermediolateral cell column in the rat. Brain ICes. 222, 129-133. LOEWY,A. D. and MCI~LL~, S. (1981) Serotonergic projections from the ventral medulla to the intermediolateral cell column in the rat. Brain Res. 21, 146-152. LOEWY, A. D., WALLACH,J. H. and McKELL~, S~ (1981) Efferent connections of the ventral medulla oblongata in the rat. Brain Res. Rev. 3, 63-80. LOVICK, T. A. (1985a) Projections from the diencephalon and mesencephalon to nucleus paragigantoeetlularis lateralis in the cat. Neuroscience 14, 853-861. LovIcK, T. A. (1985b) Ventrolateral medullary lesions block the antinociceptive and cardiovascular responses elicited by stimulating in the dorsal periaqueductal grey matter in rats. Pain 21, 241-252. LovlcK, T. A. (1986) Analgesia and the cardiovascular changes evoked by stimulating neurones in the ventrolateral medulla in rats. Pain 25, 259-268. LOVlCK, T. A. (1987) Differential control of cardiac and vasomotor activity by neurones in nucleus paragigantocellularis lateralis in the cat. J. Physiol. 3159, 23-35. LOVICK,T. A. (1988) Convergent afferent inputs to neurones in nucleus paragigantocellularis lateralis in the caL Brain Res. 456, 483-487. LOvICK, T. A. (1992a) Inhibitory modulation of the cardiovascular defence response by the ventrolateral periaqueductal grey matter in rats. Expl Brain Res. 89, 133-139. LovlcK, T. A. (1992b) Midbraln influences on ventrolateral medullo-spinal neurones in the rat. Expl Brain Res., in press. LovlcK, T. A. and LI, P. (1989) Integrated function of neurones in the rostral ventrolateral medulla. Prog. Brain Res. 81, 223-232. LOVICK,T. A. and Lucre, B. M. (1991) The defence reaction and inhibition of viscerosomatic reflexes. In: Proceedings

CARDIOVASCULARAND PAIN REGULATION Vlth Worm Congress on Pain, pp. 385-389. Eds. M. R. BOND, J. E. CHATTONand C. J. WOOLF.El~vier, Holland. Lowc[, T. A., SMITH, P. R. and HILTON, S. M. (1984) Spinally-projecting neurones near the ventral surface of the medulla in the cat. J. auton, nerv. Sys. 11, 27-33. Lu, G. W. (1983) Characteristics of afferent fibre innervation on acupuncture points Zusanli. Am. J. Physiol. 245, Rt06-R612. MCCALL, R. B. (1984) Evidence for a serotonergically mediated sympathoexcitatory response to stimulation of medullary raphe nuclei. Brain Res. 311, 131-139. MCCALL, R. B. (1986) Lack of involvement of GABA in baroreceptor-mediated sympathoinhibition. Am. J. Physiol. 250, R1064-1073. MCCALL, R. B. and CLEMENT,M. E. (1989) Identification of serotonergic and sympathetic neurones in medullary raphe nuclei. Brain Res. 477, 172-182. MCCALL, R. B. and HUMPHREY,S. J. (1985). Evidence for GABA mediation of sympathetic inhibition evoked from midline medullary depressor sites. Brain Res. 339, 356-360. MCCARTY, R. and KOPIN, I. J. (1978) Alterations in plasma catecholamines during acute stress in spontaneously hypertensive and Wistar-Kyoto normotensive rats. Life Sci. 22, 997-1006. MAGOUN,H. W. and P-d-nNES,R. (1946) An inhibitory mechanism in the bulbar reticular formation. J. Neurophysiol. 9, 165-171. M~dXNER, W., BOSSUT, D. F. and WHITSEL, E. A. (1991) Evaluation of vagal afferent modulation of the digastric reflex in cats. Brain Res. 560, 55-62. MAIX~ER,W. and RANDICH,A. (1984) Role of the fight vagal nerve trunk in antinociception. Brain Res. 298 374-377. M~aY,-~SR,W., Touw, R. B., BRosY, M. J., GEBrtART,G. and LONG, J. P. (1982) Factors influencing the altered pain perception in the spontaneously hypertensive rat. Brain Res. 237, 137-145. MANCIA, G. and ZANCHETTI,A. (1981) Hypothalamic control of autonomic functions. In: Handbook o f the Hypothalamus, Vol. 3, Part B. Behavioural Studies, pp. 147-202. Eds. V. P. MORGANEand J. PANSKEPP. Marcel Dekker, New York. MANCIA, G., BACCELLI, G. and ZANCHETTI, A. (1972) Haemodynamic responses to different emotional stimuli in cats: patterns and mechanisms. Am. J. Physiol. 223, 925-933. MARCHAND,J. E. and HAGINO,N. (1983) Afferents to the periaqueductal gray in the rat. A horseradish peroxidase study. Neuroscience 9, 95-106. MARTIN, J. E., SUTHERLAt,ag, C. J. and ZBROZYNA,A. W. (1976) Habituation and conditioning of the defence reactions and their cardiovascular components in dogs and cats. Pflugers Arch. 365, 37-47. MASON,P., STRASSMAN,A. and MAcmwIcz, R. (1985) Pontomedullary raphe neurons: monosynaptic excitation from midbrain sites that suppress the jaw opening reflex. Brain Res. 329, 384-389. MAYER, D. J., WOLFE, T. L., AKIn, H., CARDER, B. and LEnV-SKIND,J. C. (1971) Analgesia from electrical stimulation in the brainstem of the rat. Science 174, 1351-1354. MELLER, S. T., LEWIS, S. J., NESS, T. J., BRODY, M. J. and GEBrL~gT,G. F. (1990) Vagal afferent-mediated inhibition of a nociceptive reflex by intravenous serotonin in the rat. I. Characterization. Brain Res. 524, 90-100. MELZACK, R. and WALL, P. D. (1965) Pain mechanisms: a new theory. Science 150, 971-979. MINSON, J. B., CHALMEgS, CAON, A. C. and PENAUD, B. (1987). Separate areas of rat medulla oblongata with populations of serotonin- and adrenaline-containing neurones alter blood pressure after L-glutamate stimulation. J. auton, nerv. Sys. 19, 39-50. MORTON, C. R. and DUGGAN, A. W. (1986) Inhibition of spinal nociceptive transmission accompanies cardiovascu-

643

lar changes from stimulation in diencephalic 'defence' regions of cats. 8ehavl Brain Res. 21, 183-188. NASHOLD,B. S., WILSON,W. P. and SLAUGHTER,D. G. (1969) Sensations evoked by stimulation in the midbmin in man. J. Neurosurg. 30, 14-24. NESTEL, P. J. (1969) Blood pressure and catecholamine excretion after mental stress in labile hypertension. Lancet 1, 692-695. OMURA, Y. (1975) Pathophysiology of acupuncture treatment: effects of acupuncture on cardiovascular and nervous systems. Acupunc. Electrother. Res. 1, 51-141. PERT, C. B. and SNYDER, S. H. (1973) Opiate receptor: demonstration in nervous tissue. Science 179, 1011-1014. PRADO, W. A. and ROBERTS,M. H. T. (1985) An assessment of the antinociceptive and aversive effects of stimulating identified sites in the rat brain. Brain Res. 340, 219-228. PRETO, G. J., CANNON,J. T. and LESESKIND,J. C. (1983) N. raphe magnus lesions disrupt stimulation-produced analgesia from ventral but not dorsal midbrain sites. Brain Res. 261, 53-57. RANDICH, A., AIMONE, L. D. and GEBHART,G. F. (1987) Medullary substrates of descending spinal inhibition activated by intravenous administration of [D-Ala2] methionine enkephalinamide in the rat. Brain Res. 411, 236-247. RANDICrI,A., PEN, K. and GEnPO,gT, G. F. (1990) Electrical stimulation of vagal afferents. II. Central relays for behavioural antinociception and arterial blood pressure decreases. J. Neurophysiol. 64, 1115-1124. PEN, K., IL~NDiCH,A. and GEnHART,G. F. (1990) Electrical stimulation of cervical vagal afferents. I. Central relays for modulation of spinal nociceptive transmission. J. NeurophysioL 64, 1098-1114. REYNOLDS,D. V. (1969) Surgery in the rat during electrical analgesia induced by focal brain stimulation. Science 164, 444--445. PdCKST~IN,S. E., NOPa~SSON,E. and THOI~N, P. (1979) Inhibition of renal sympathetic nerve traffic from cardiac receptors in normotensive and spontaneously hypertensive rats. Acta physiol, scand. 106, 17-22. RIzvl, T. A. (1991) Connections between the central nucleus of the amygdala and the midbrain periaqueductal gray: topography and reciprocity. J. comp. Neurol. 303, 121-131. ROBINSON,R. L., CULBERSON,J. L. and CARMICHAEL,S. W. (1983) Influence of hypothalamic stimulation on the secretion of adrenal medullary catecholamines. J. auton. nerv. Sys. 8, 89-96. ROGEgS, R. J. (1978) Influence of intra-amygdaloid opiate injection on shock threshold, tail flick latencies and open field behaviour in rat. Brain Res. 153, 211-216. SCHMITT,P., ECLANCHER,F. and KARLI,P. (1974) Etudes des syttmes de renforcement negatif et de renforcement positif au niveau de la substance grise centrale chez le rat. Physiol. Behav. 12, 271-279. SCHULTZ,H. D., GARDNER,D. G., DESCHEPPER,F., COLERIDGE, H. M. and COLERIDGE,J. G. (1988) Vagal C-fibre blockade abolished sympathetic inhibition by atrial natriuretic factor. Am. J. Physiol. 255, R6-RI3. SCHLITZ, M., DE AGUIAR,J. C. and G'RAEFF, F. G. (1985) Antiaversive role of serotonin in the dorsal periaqueductal grey matter. Psychopharmacology 85, 340-345. SEMANENKO, F. and LUMB, B. M. (1992) Projections of anterior hypothalamic neurones to the dorsal and ventral periaqueductal grey in the rat. Brain Res. 582, 237-245. SHEPHERD,J. T. and MANC1A,G. (1986) Reflex control of the human cardiovascular system. Rev. Physiol. Biochem. Pharmac. 105, 1-100. Srncu, B. C., ANDERSSON,S. A. and THOREN,P. (1982) Endorphin mediated increase in pain threshold induced by long lasting exercise in rats. Life Sci. 30, 833-840.

644

T.A. LOVlCK

SIDALL, P. J. and DAMPNEY, R. A. L. (1989) Relationship between cardiovascular neurones and descending antinociceptive pathways in the rostral ventrolateral medulla of the cat. Pain 37, 357-364. SPYER, K. M. (1981) Neural organisation and control of baroreceptor reflex. Rev. Physiol. Biochem. Pharmac. 88, 24-124. STODDARD, S. L., BEGDALL, V. K., CONN, P. S. and LEVIN, B. E. (1987). Increases in plasma catecholamines during naturally elicited defensive behaviour in the cat. J. auton. nerv. Sys. 19, 189-197. STODDARD-APTER, S. L., SIEGEL,A. and LEVIS, B. E. (1983) Plasma catecholamine and cardiovascular responses following hypothalamic stimulation in the awake cat. J, auton, nerv. Sys. 8, 343-360. SUN, M. K. and GUYENET, P. (1985) GABA-mediated baroreceptor inhibition of reticulo-spinal neurons. Aim. J. Physiol. 249, R672-680. TAKAYAMA, K., OJAOA, J. and MIURA, M. (1990) Evidence that neurons in the central amygdaloid nucleus directly project to the site concerned with circulatory and respiratory regulation in the ventrolateral nucleus of the cat: a WGA-HRP study. Neurosci. Lett. 109, 241-246. THOREN, P., MARC, A. L., MORGAN, D. A , O' NELL, T. P., NEEDLEMAN, P. and BRODY, M. J. (1986) Activation of vagal depressor reflexes by atriopetins inhibits renal sympathetic activity. Am. J. Physiol. 251, HI252-H1259. THURSTON, C. L. and RANDICH, A. 0990) Acute increases in arterial blood pressure produced by occlusion of the abdominal aorta induces antinociception--peripheral and central substrates. Brain Res. 519, 12-22. THOMPSON, R. L. and CASSELL, M. D. (1989) Differential distribution and non-collateralization of central amygdaloid neurons projecting to different medullary neurons. Neurosci. Lett. 97, 245-251. TIMMS, R. J. (1981) A study of the amygdaloid defence reaction showing the value of Althesin anaesthesia in studies of forebrain function. Pflugers Arch. 391, 49-56. UNGER, T., CAROLUS,S., DEMMER,T. G., GANTEN, D., LANG, R. E., MASER-SMITH,C., STEINBERG,H. and VEELKEN, R. (1988) Substance P induces cardiovascular defence reaction in the rat: pharmacological characterisation. Circulation Res. 63, 812-820. VAN BOCKSTAELE,E., ASTON-JONES, PIERIBONE,V. A., ENNIS, M. and SHIPLEY, M. T. (1991) Subregions of the periaqueductal gray topographically innervate the rostral ventral medulla in the rat. J. comp. Neurol. 309, 305-327. VIKEN, R. J., JOHSON,A. K. and KNUTSON,J. F. (1991) Blood pressure, heart rate and regional resistance in behavioural defence. Physiol. Behav. 50, 1097-1101.

VlVEROS, O. H. and WmSON, S. P. (1983) The adrenal chromaffin cell as a model to study the co-secretion of enkephalins and catecholamines. J. auton, nerv Sys. 7, 41-58. VOLPE, M., CUOCOLO, A., VECCHIONE, F., MELE, A. F.~ CONDORELLI, i . and TRIMANO,B. (1987) Vagal mediation of the effects of atrial natriuretic factor on blood pressure and arterial baroreflexes in the rabbit. Circulation Res. 60, 747-755. WALL, P. D. (1967) The laminar organisation of dorsal horn and effects of descending impulses. J. Physiol., Lond. 188, 403-423. WALLACE, n . i . , MAGNUSSON,D. J. and GRAY, T, S. (1989). The amygdalo-brainstem pathway: selective innervation of dopaminergic, noradrenergic and adrenergic cells in rat. Neurosci. Lett. 97, 252-258. WANG, Q., MAD, L. and HAN, J. S. (1990) The arcuate nucleus of hypothalamus mediates low but not high frequency electroacupuncture in rats. Brain Res. 513, 60~6. WANG, W. H. and LOVlCK, T. A. (1992) Rote of medullary raphe nuclei in the inhibition of rostral ventrolateral medullary neurones evoked from the ventrolateral periaqueductal grey matter in anaesthetised rats. J. Physiol. 446, 521P. WENDELL, O. T. and BENNET, B. (1981) The occurrence of analgesia in an animal model of hypertension. Life Sci. 28, 515-521. YAKSrt, T. L., YEUNG, J. C. and RUBY, R. A. (1976) Systematic examination in the rat of brain sites sensitive to the direct application of morphine: observation of differential effects within the periaqueductal gray. Brain Res. 114, 82-103. YAO, T., ANDERSSON,S. and THOREN, P. (1982) Long-lasting cardiovascular depressor response following sciatic stimulation in spontaneously hypertensive rats. Evidence for the involvement of central endorphin and serotonergic systems. Brain Res. 244, 295-303. YARDLEY, C. P. and HILTON, S. M. (1987) Vasodilatation in hind-limb skeletal muscle evoked as part of the defence reaction in the rat. J. auton, nerv. Sys. 19, 127-136. YEUNG, J. C., YAKSrL T. L. and Ruox, T. A. (1977) Concurrent mapping of brain sites for sensitivity to the direct application of morphine and focal electrical stimulation in the production of antinociception in the rat. Pain 4, 23-40. YOUNG, R. F. (1989) Brain and spinal stimulation: how and to whom? Clio. Neurosurg. 35, 429-447. ZrtANG, S. P., BANOLER,R. and CARmVE,P. (1990) Flight and immobility evoked by excitatory amino acid microinjection within distinct parts of the subtentorial midbrain periaqueductal gray of the cat. Brain Res. 520, 73-82.