Neural Basis of Vomiting

Chapter 2

Neural Basis of Vomiting

2.1. Medullary Structures Early workers, notably Thumas (1891), Hatcher and Weiss (1922, 1923) and Koppanyi (1930), by observing the effects of ablative procedures on the brain stem on drug-induced vomiting in dogs, obtained evidence for the existence of a vomiting centre in the medulla« These studies were reviewed by Borison and Wang (1953). Borison and his associates, by employing more precise procedures, were able to explore more effectively the organization of the central emetic mechanism. By applying electrical stimulation to portions of the lower brain stem in the decerebrate cat they determined the position of the bilateral vomiting centre, in the dorsal portion of the lateral reticular formulation of the medulla (Borison, 1948; Borison and Wang, 1949). Further, they found that superficial lesions of the medulla in dogs abolished the vomiting response to apomorphine and certain cardiac glycosides given intravenously, without affecting the response to copper sulphate given orally. Deeper lesions also involving the lateral formation impaired the response to both intravenous apomorphine and oral copper sulphate (Wang and Borison, 1950, 1952). There was thus identified a superficial chemoreceptor trigger zone for vomiting (CTZ) which functions as a receptor site for centrally-acting emetic agents. In low doses, oral copper sulphate excites receptors in the gastrointestinal tract which activate the vomiting centre directly through afferent pathways in the autonomie nerves. When the vomiting centre in dogs was destroyed by implantation of radon seeds into the lateral reticular formation, leaving the CTZ undamaged, the thresholds to a variety of emetic agents including intravenous apomorphine and digitalis, and oral copper sulphate, were raised (Globus et al., 1952; Wang and Borison, 1951). It was apparent, therefore, that the CTZ has a receptor, not an integrative function and that it communicates with the integrative vomiting centre (VC) (Borison and Wang, 1953). Borison (1959) further demonstrated the functional distinction between the CTZ and VC in the cat by showing that ablation of the CTZ abolished the vomiting response to cerebral intraventricular injection of adrenaline and apomorphine, while the response to oral copper sulphate remained unimpaired. The vomiting centre, in the lateral reticular formation, is ideally placed to exercise its role of co-ordinating the somatic and visceral efferent functions associated with vomiting. It lies in close proximity to the following regulatory foci, listed by Borison and Wang (1953); the spasmodic respiratory centre, the respiratory and expiratory centres, the vasomotor centre, the salivatory nuclei,

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the vestibular nuclei and the bulbofacilitatory and inhibitory systems· ffA consideration of the vomiting act shows that all the represented activities are involved in its motor expression." In order to determine precisely the location of the CTZ in the cat, Borison and Brizzee (1951) made a variety of superficial medullary lesions, with the use of electrocautery, in numerous animals and observed the effects of the lesions on the ability to vomit in response to intravenous cardiac glycosides· They were able to define the CTZ as bilateral portions of tissue, less than one cubic millimetre in size, on either side of the fourth ventricle, contiguous medially with the area postrema (see Fig. 2 ) . In the dog, the CTZ was less clearly definable. Brizzee and Neal (1954), in histological studies, found the area postrema in the cat to be highly vascularized and to contain neuronal elements, with loose bundles of fibres passing between the area postrema and the adjacent medullary tissue: they concluded that the morphology of the area postrema is consistent with a chemoreceptor function. The area postrema was found to be present in all those mammalian species in which a study was made (Clémente and Van Breemen, 1955) of the floor of the fourth ventricle, though it may vary in size and shape. Generally, it is a highly vascularized, paired structure, lying astride the opening of the spinal canal into the fourth ventricle, and is bathed by the cerebrospinal fluid. In rodents and lagomorphs it is a central, unpaired structure. Wislocki and Leduc (1952) showed that the blood-brain barrier in the area postrema is deficient relative to that of other medullary structures and that the area is unusually permeable to blood-borne substances. Roth and Yamamoto (1968) described the microcirculation in the rat: the area postrema has direct access to arterial blood, and the circulatory structure is such that bilateral occlusion of the vertebral or the posterior inferior cerebellar arteries would be necessary to isolate it from its source. These authors concluded that the vascular pattern is well suited to neurosecretory or chemosensory functions. It has not been possible to identify specialized chemoreceptors in the area postrema histologically, though De Kock (1959) suggested that certain cells bear a resemblance to receptor cells of the carotid body. Much effort has been expended on histological studies of the connections and neuronal projections of the area postrema, to determine inter alia whether pathways to the lateral reticular formation, the site of the vomiting centre, could be defined. Morest (1960) made studies in a variety of species, employing Golgi methods. He was able to identify in the area postrema, in addition to other cell types, many cells with the features of mature neurons; the area contained a plexus of fine nerve fibres and fibres were seen to enter and leave the plexus, some in the direction of the nucleus solitarius. Morest (1967) further studied the projections of the area postrema and the nucleus solitarius by making lesions in these structures and observing the extent of fibre degeneration. He observed that neurons in the area postrema project mainly ipsilaterally to the dorsal and medial regions of the medial nucleus solitarius. Significantly, projections of the nucleus solitarius were found to the dorsal and lateral reticular formation of the medulla; hence it would appear that an anatomical, neuronal basis exists for communication between the CTZ and VC. Whether any axons pass directly from the area postrema to the lateral reticular formation without synapsing is not known. Physiological evidence for a neuronal connection from the CTZ to the VC was claimed by Iwase (1971), who elicited vomiting in the dog by electrical stimulation of the CTZ. In the same study Morest (1967) was able to observe that ascending pathways in the dorsal and lateral colums of the spinal cord project to the area postrema, with axons ramifying to the anterodorsal part of the area, corresponding to the CTZ. It is possible that this pathway might play a role in the physiology of vomiting, under the influence of peripheral or visceral stimuli. Concerning other

The Physiology and Pharmacology of Emesis

Fig,

2.

Dorsal view of the cat medulla oblongata illustrating the approximate morphological relationship of functional components in the vomiting control mechanism. The right half of the figure shows surface structures exposed by removal of the cerebellum. The CTZ (chemoreceptor trigger zone for emesis) is contained in the area postrema on the caudal margin of the IVth ventricle. The left half of the figure shows subsurface emetic control components in relation to the tractus solitarius (TS) marked in solid black. The cylindrical vomiting centre (VC) lies immediately beneath TS while the retching centre (RC) is situated dorsal and lateral to TS. The large respiratory centre (IC) is situated deepest, in the medial reticular formation. Reproduced from Borison and McCarthy (1983) Drugs 25 (Suppl. 1 ) , 8-17, with permission.

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relevant afferent pathways, the dorsal and lateral region of the reticular formation, site of the VC, receives a prominent projection from the lateral spinal cord. Further, the region of the nucleus solitarius that projects to the reticular formation is that receiving primary glossopharyngeal and vagal afférents. Morest suggested that the receptor functions of the area postrema could be integrated in the nucleus solitarius in relation to the sensory inputs of the vagus nerve. Morest further found projections of the nucleus solitarius to the dorsal vagal nucleus in addition to those to the lateral reticular formation, already mentioned; both, he suggested, may be concerned with cardio-respiratory and alimentary autonomie reflexes. No direct projections from the nucleus solitarius to the thalamus were found. Morest (1967) therefore suggested that enteroceptive signals, before reaching the thalamus, may be integrated in the reticular formation where they are subject to modification by somatic, vestibular or auditory inputs. Gwyn and Leslie (1978) were able to show, following unilateral excision of the nodose ganglion in the cat, that fine terminal degeneration occurred in the rostro-lateral portion of the area subpostrema, which lies in or near the region considered to be the CTZ for vomiting. They could therefore conclude that vagal afferent fibres reach the neighbourhood of the CTZ rather than terminating in the nucleus solitarius and that this vagal projection might play a primary role in the emetic response. Borison et al. (1975) recorded electrical activity from the vicinity of the area postrema in the cat by means of microelectrodes, restricting the field of exploration to the area postrema and structures one millimetre deep and lateral to it. Units found to fire in response to somatosensory stimuli, or synchronously with the respiratory rhythm, were excluded from consideration. There remained units, clustered around the margin of the area postrema (CTZ) firing spontaneously at low frequency; such units were seldom found in the body of the area postrema. The frequency of firing markedly accelerated in response to the centrally-acting emetic drug ouabain given intravertebrally and to ATP, a possible neurotransmitter substance, given by the same route. Evidence of chemoreceptor activity by units of the CTZ was thereby obtained. Surprisingly, the electrical response to apomorphine was indistinct. In view of the absence of unit potentials from the body of the area postrema, these authors introduced the concept that the organ might perform the role of a chemical transducer that activates the CTZ. It is evident from the work of Brizzee and Marshall (1960) in the cat and Pi and Peng (1971) in the dog that the capacity for reflex vomiting through stimulation of gastrointestinal receptors is present within a very few days of birth and hence the VC is competent at that time. In contrast, Borison and Borison (1973) found in the cat that the ability to vomit in response to agents known to act at the CTZ, for example the cardiac glycoside deslanoside, does not develop until the age of three to four weeks. In morphological studies they established that the latter ability is dependent upon the full maturation of fibre connections in and through the area postrema; such maturation is not complete until that age. The functional significance of the area postrema in man was established by Lindstrom and Brizzee (1962), who made lesions in the area postrema of five patients with intractable vomiting due to inoperable brain tumours; these patients were thereby relieved of vomiting symptoms, and they also became refractory to apomorphine. Speculation by several authors that the area postrema might have a receptor role in connection with functions other than vomiting, (for example: control of food intake; effects of serotonin on the electroencaphalogram; cardiovascular effects of angiotensin) were reviewed by Borison (1974); none of these has been

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proved. Cats with chronic lesions of the area postrema appeared to suffer from no gross deficiency other than an inability to respond to centrally-acting emetic agents, typically the opiates and cardiac glycosides: the ability to vomit in response to stimulation of afferent systems in the periphery, for example the gastrointestinal tract, remained unimpaired. In the same paper, Borison reviewed speculatively the topology of the area postrema, its ultrastructural features and its barrier properties, in relation to function. Certain medullary sites contain chemoreceptors which respond to local increases in carbon dioxide or hydrogen ion concentration with an effect on respiration; ventilation is increased. Hori et al. (1970) showed that in the rat such sites are confined to the ventrolateral surface of the medulla, confirming earlier findings in the cat (Mitchell et al. 1963): no such response was elicited from the area postrema.

2.2. Efferent Systems In early work, direct electrical stimulation of the VC was shown to result in prompt, projectile vomiting without prior retching, similar to that observed clinically in association with elevated cerebrospinal fluid pressure, while strong, rhythmic respiratory movements reminiscent of retching were elicited by stimulation of the descending vestibular root, so that a physiological distinction was made between retching and expulsion (Borison and Wang, 1953). More recently, Kimura elicited retching in response to electrical stimulation within a comparatively broad area of the medulla (Iwase, 1971). This distinction, in terms of muscular activity of the diaphragm, was underlined by recent work (Monges et al., 1978) already described in Chapter 1. Monges et al. (1974) recently stated the concept that during vomiting the normal pattern is superceded, with inhibition of the respiratory centres, and that "motor programming" passes under the control of the VC, so that motoneurones normally associated with respiration are employed in the vomiting function. The somatic efferent nervous pathways are known. Stewart et al. (1977) obtained confirmatory evidence that the VC co-ordinates the activity of medullary centres to provide the visceral efferent components in vomiting, in addition to the somatic. The orally-migrating myoelectric pattern in the small intestine characteristic of emesis (Chapter 1.2) was observed by these authors as a stereotyped response following intraventricular injection of morphine, apomorphine or adrenaline, but it was not elicited when similar doses of these agents were administered peripherally. Further evidence that the intestinal myoelectric response is of central rather than peripheral origin was provided by the observation that morphine and adrenaline, when administered peripherally, had opposing effects on intestinal mechanical and electrical activity. It is of interest that the migrating spike-burst but not the emesis due to intraventricular adrenaline was selectively abolished by atropine. Thus, apparently, atropine can abolish the visceral efferent response of the intestine during vomiting without affecting the somatic efferent components of the motor programme. According to Stewart et al. this observation may be of clinical importance. The emetic agents employed in this study act at the chemoreceptor trigger zone: the emetic effects of morphine and apomorphine were abolished by intraventricular naloxone, an opiate receptor antagonist, while those of adrenaline were abolished by intraventricular phentolamine, an a-adrenergic blocking agent. The authors state that the efferent pathways involved are unknown, though they cited the earlier finding of Gregory (1947) that vagotomy, but not splanchnic nerve section, abolished motility changes in the dog intestine in vomiting induced by apomorphine. The efferent systems involved in the regulation of the regional changes in gastric tone and motility associated with vomiting, already described

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(Chapter 1.2) were considered in detail by Abrahamsson and associates (Abrahamsson, 1973; Abrahamsson et al« , 1973), who reviewed the literature relevant at that time. It is noteworthy that the pattern of behaviour of the stomach seems to be the same whatever the cause of the vomiting, supporting the concept of central control. Contractile behaviour of the organ occurs against a background of spontaneous myogenic activity initiated by pacemaker action (Weber and Kohatsu, 1970) and further, gastric movements are influenced by a complex array of humoral factors which will be briefly considered later in this paper. Nevertheless, it is apparent that the extrinsic nerve supply plays an important part in influencing gastric muscular activity. Excitation is conveyed by cholinergic neurons of the plexus of Auerbach, controlled by preganglionic vagal efferents: these are subject to presynaptic inhibition by adrenergic efferents (c.f. Seno et al., 1978; Vizi et al., 1978) which, according to Abrahamsson, are of minor importance in regard to the relaxation of the corpus and fundus associated with vomiting. This relaxation is mediated by non-adrenergic, non-cholinergic fibres of the vagus whose inhibitory transmitter substance was suggested to be adenosine triphosphate (ATP) or a related nucleotide. The topic of such "purinergic" nerves was reviewed by Burnstock (1972). Non-adrenergic, non-cholinergic inhibitory nerves are widely distributed in the body and have been demonstrated at many sites, including the lower oesophageal sphincter (Goyal and Rattan, 1975) and the pylorus (Anuras et al., 1974). There has been speculation that vasoactive intestinal peptide (VIP) might have a role as a peptidergic inhibitory neurotransmitter of these nerves (Strunz et al., 1977). Stockley (1977) demonstrated that ATP is unlikely to act as a non-adrenergic inhibitory transmitter in isolated human taenia coli. ATP was shown to be excitatory to stomach muscle through a direct effect in certain species (Burks and Grubb, 1977), although Lefebvre and Willems (1979) observed gastric relaxation in the dog in response to ATP. Hence it would seem that the inhibitory transmitters may differ in nature according to the gastrointestinal site and the species. A role of dopamine as the physiological neurotransmitter for receptive relaxation of the stomach in the dog was suggested by Valenzuela (1976); dopamine caused a decrease in intragastric pressure, not blocked by a- or 3-receptor antagonists, but blocked by pimozide and metoclopramide, two known dopaminergic antagonists. Lanfranchi et al. (1977) demonstrated that dopamine induces an inhibitory effect on the motor activity of the human gastric antrum which could be prevented by sulpiride, a specific dopaminergic antagonist. Ennis et al. (1977) found that dopamine inhibited cholinergic transmission in the isolated ileum preparation of the guinea pig. In further experiments with isolated tissue from the upper parts of the gastrointestinal tract, these authors demonstrated that relaxation of the gastro-oesophageal junction was induced by dopamine and by noradrenaline; here the effect of dopamine was blocked by the antiemetic drug and dopamine antagonist domperidone but, remarkably, not by pimozide. In contrast to the results at the gastro-oesophageal junction, domperidone failed to block the relaxatory effects of dopamine at the gastroduodenal junction (Ennis et al., 1978), Hence it is apparent that in the gut, as in the central nervous system (Kebabian and Kebabian, 1978; Cools, 1978) different categories of pharmacologically distinct dopamine receptors exist. Inhibitory, histamine receptors were detected in the chicken ileum (Chand and De Roth, 1978). It was determined that neither histamine nor cholecystokinin plays any significant role in the inhibitory response of the canine pylorus mediated by the vagus, nor in the atropineresistant spontaneous pyloric motor activity (Telford et al., 1979).

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The effects of neurotransmitters, inhibitory or excitatory, on gastrointestinal muscle have been shown to interact with those of a number of humoral factors and examples may be cited from the recent literature. Thus prostaglandin-induced intestinal motility in humans was observed to be modulated through vegetative neurotransmitters; cholinergic activity intensified and 3-adrenergic activity inhibited such motility (Schmidt et al., 1978). Adrenergic responses of guinea-pig ileum were inhibited by prostaglandins (Bartho, 1978). Substance P appears to be a modulator of neuronal activity in the myenteric plexus (Katayama and North, 1978): it is of interest that the spasmogenic actions of substance P on isolated guinea-pig ileum were inhibited by the dopamine antagonists haloperidol, pimozide and droperidol (Elliot and Glen, 1978). Metoclopramide increased gastric motility in the conscious rat, despite simultaneous infusion of secretin or intraduodenal infusion of HC1; thus it may be that inhibitory dopamine receptors in the gut limit the sensitivity of the gut to low concentrations of agonists (Blower et al., 1977).

2.3. Afferent Systems A body of evidence from animal experiments, some of which has already been referred to, permits a classification of the afferent systems determining the degree of excitation of the VC. Probably not all are known. Knowledge of excitatory systems predominates over that of inhibitory ones. Afferent pathways have proved difficult to study since more than one pathway may be activated from a single organ, and an emetic agent may act at more than one site. Pathways that influence the VC are known to originate in (i) the gastrointestinal tract, (ii) the heart and other viscera, (iii) the chemoreceptor trigger zones (CTZ), (iv) the labyrinth and (v) supramedullary sites of the CNS.

2.3.1.

Gastrointestinal Tract

Early studies of pathways from the gastrointestinal tract were reviewed by Borison and Wang (1953). Irritation or distension of the small intestine was more effective in inducing emesis than similar stimulation of the stomach. Generally, vagal afférents were found to be more important than those in the sympathetic. Vomiting could be readily elicited through electrical stimulation of the central ends of the vagal branches of the stomach. The local emetic action of mustard on the gastric mucosa could be prevented by division of the vagi, but not by division of the splanchnic nerves. The vomiting due to distension of pyloric pouches could be abolished by transthoracic vagotomy9 but not by sympathectomy. The vomiting due to ingestion of copper sulphate was dependent upon both vagal and abdominal sympathetic afférents, but vagal transmission was the more important· However, in vomiting resulting from intestinal distension, sympathetic and not vagal afférents were found to be involved. In a more recent study concerned with afférents from the upper part of the tract Hayashi (ref. in Iwase, 1971) observed swallowing in the decerebrate cat in response to pressure or electrical stimulation of the area of the root of the tongue or the rear wall of the pharynx; stronger stimulation evoked vomiting.

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Thus vomiting resulted from abnormal stimulation of the pharyngeal branch of the vagus and glossopharyngeal nerves. It is apparent that swallowing and vomiting have certain pathways and medullary mechanisms in common. Bieger et al., (1978) state that these functions share afferent and efferent mechanisms, and also are represented co-extensively at all levels up to and including the orbitofrontal cortex. Hayashi further recorded the degree of mouth opening during vomiting and observed a relationship with the stickiness of the vomitus, mediated by the pharyngomandibular reflex (Iwase, 1971). Abrahamsson (1973) reviewed recent work concerned with gastric afférents conveyed both in the vagus and the sympathetic. Studies on vagal afférents revealed two distinct categories of gastric mechanoreceptor, one slowly adapting and a second rapidly adapting, with chemoreceptor properties as well. The slowly adapting receptors are activated both by passive distension of the viscus and by isometric contraction in the receptor area and were therefore termed tension receptors. The rapidly adapting receptors are activated by brushing the mucosa and the same units also respond to acidic and alkaline solutions. Gastric receptors with afférents in the splanchnic nerves were investigated by electrophysiological techniques. Mechanoreceptors were identified in the stomach, mesentery and intestinal serosa, discharging in response to distension and rapidly adapting to repeated stimuli. Also, gastric receptors were found responding to distension and contraction of the antrum. In agreement with earlier observations (vide supra) Sharma et al. (1972) concluded that the afferent pathways concerned in emesis due to intestinal obstruction travel through the sympathetics to the spinal cord, whence they traverse to the VC: such emesis in the dog was not prevented by bilateral transthoracic supradiaphragmatic vagotomy, but was blocked by spinal cord transection at Ci-Ti. Kayashimi and associates (1978a,b) measured the emetic threshold in the dog to copper sulphate given orally at various sites in the gastrointestinal tract. Sensitivity was highest in the lower duodenum, while in the stomach the pyloric antrum was most sensitive and the corpus had low sensitivity. The ileum was insensitive. General projections of afferent fibres of the vagus in the cat were studied by Gwyn and co-workers (Gwyn and Leslie, 1978, 1979; Gwyn et al., 1979). Such afférents were known to terminate in the medial and lateral parts of the solitary nucleus and in the commissural nucleus. An additional, dense vagal projection to the area subpostrema was found. Furthermore, by means of axonal transport of horseradish peroxidase injected into the stomach wall, fibres and terminals were labelled bilaterally in the area subpostrema and more ventral parts of the solitary nucleus. Thus, the first morphological evidence was provided of the projection of gastric vagal afférents to an area implicated in gastric functions and indeed, in vomiting (Chapter 2.1). Injection of [3H]leucine or horseradish peroxidase into the nodose ganglion, probable site of the emetic action of the veratrum alkaloids, revealed similar central projections. A relevant physiological study by Harding and Leek (1973) may be noted: "afferent-like activity" was observed at points in the solitary nucleus subadjacent to the area postrema in the sheep, in response to distension of the stomach. The important histochemical studies of Morest, demonstrating pathways in the medulla, were described in Chapter 2.1. A study by Zabara et al. (1972) introduced the concept of neuroinhibition in the regulation of emesis. Emesis, preceded by retching, could be induced in the dog by electrical stimulation of the abdominal vagus nerves at the supradiaphragmatic level. Failure to produce retching or emesis by similar stimulation of the cervical vagus trunk suggested either that the abdominal vagal emetic afferent does not course in the cervical vagus, or that inhibitory fibres

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are present. Since the retching and emesis resulting from stimulation of the supradiaphragmatic vagus could be prevented either by transection of the cervical vagus or by simultaneous stimulation of the cervical vagus trunk, it was apparent that inhibitory afférents are present. That the inhibitory pathway involves pulmonary afférents was suggested by the observation that hyperventilation occurred with stimulation of the cervical vagus trunk. These workers maintained that the excitatory system involving the VC and CTZ, which has been investigated extensively, acts in conjunction with an inhibitory system so that emesis is normally prevented by a dominance of inhibition over excitation. They pointed out that apnoea is compatible with retching and emesis, and hyperventilation with inhibition. This could be considered analogous to the reciprocal inhibition occurring in the spinal cord, in connection with the contraction of antagonist muscles. It appeared that the locus of the inhibition is not directly on the retching or emetic centres since it was not possible to inhibit emesis after its initiation. Presumably, the locus could be in the solitary nucleus or at some intermediate synapse on the pathway to the retching or the vomiting centre.

2.3.2.

Heart and Other Viscera

Borison and Wang (1953) referred to vomiting resulting from distension of the bile-duct and gall-bladder, involving both vagal and splanchnic afférents, and to that resulting from irritation of the visceral peritoneum, involving pathways in the same nerves. Compression of coronary vessels caused vomiting, but the path was unknown. Abrahamsson and Thorén (1973) observed that electrical stimulation of the right cardiac nerve in the cat resulted in bradycardia, hypotension and also gastric relaxation followed by vomiting. Intrapericardial nicotine and coronary occlusion had similar effects. The gastric relaxation upon afferent cardiac nerve stimulation was abolished by dividing the right vagus caudad to the cardiac nerve and the left vagus in the neck, showing that vagal afférents mediated the effect. It was concluded that vomiting can be elicited by thin vagal cardiac efferents, probably of ventricular origin. The authors suggested that this might explain the nausea and vomiting in coronary infarction and in vaso-vagal syncope in man. öberg and Thorén (1972) presented evidence that vaso-vagal reactions can be precipitated by increased activity in left ventricular receptors, for example when left-ventricular filling becomes very poor. At an early date Barclay (1936b) described a relaxation of the stomach on X-ray in standing patients who were just about to faint and, accordingly, this could perhaps be due to a reflex from heart receptors. Abrahamsson and Thorén also suggested that left-ventricular receptors may play a part in the induction of vomiting by veratrum and digitalis alkaloids, though earlier Borison and Fairbanks (1952) deduced that the veratrum alkaloids act at the nodose ganglion, since only section of the vagus above the ganglion abolished the response.

2.3.3.

Chemoreceptor Trigger Zone

The CTZ has been stated to be the site of the emetic action of many blood-borne substances, including drugs such as apomorphine, morphine, the ergot alkaloids, the digitalis glycosides, nitrogen mustard and anaesthetics, and of numerous metabolites and endogenous substances; further, the zone has been implicated in the vomiting response to radiation exposure and, remarkably, in that due to motion in an essential role (Gibbs, 1976; Borison and Wang, 1953). In view of the anatomical and electrophysiological evidence of neuronal connections with theVC, considered in Chapter 2.1, the zone may be regarded as a specialized, central sensory apparatus which forms part of an afferent system subserving the

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vomiting reflex. Recently, Lee et al. (1978) listed emetic drugs acting principally at the CTZ; these included laevodopa, hydergine, morphine, ouabain, acetylstrophanthidin, nicotine, adrenaline, emetine and sodium salicylate. From the varied nature of the substances which are excitatory to the CTZ, it is reasonable to assume that numerous, specific chemoreceptors are present. The sensitivity of the zone to a given emetic agent can vary according to the species. In this connection, special interest attaches to the action of apomorphine, which was shown to induce vomiting solely through the CTZ by all routes of administration (Borison and Wang, 1953). The drug is ineffective in pigs, horses, donkeys and domestic fowl (Lindstrom and Brizzee, 1962) and monkeys do not vomit even in response to a lethal dose (Browne and Sparks, 1961); the drug is not consistently effective even in large doses in cats (Borison et al., 1958) which frequently respond with states of hyperactivity instead of vomiting (Borison and Wang, 1953). In contrast, apomorphine is highly effective in dogs (Borison and Wang, 1953), and in man a dose of 0.05 mg kg" given subcutaneously consistently caused vomiting (Proctor et al., 1978). The greater sensitivity of the CTZ in the dog, compared with that in the cat, has been shown in numerous instances: in the early work of Hatcher and Weiss (1923), in which 27 substances were applied to the floor of the fourth ventricle in both species, 13 of the substances caused vomiting in the dog and only one, brucine sulphate, in the cat. The ergot alkaloids, which induce vomiting in the dog, are ineffective in the cat (Borison et al., 1958) and a greater sensitivity of dogs to lobeline or nicotine was noted (Laffan and Borison, 1957). Thus the range of receptor types present in the CTZ is more extensive in some species than in others. Clearly the CTZ of the dog is more amply supplied than that of the cat. Further, where an emetic agent is effective in more than one species, the relative contributions of the various afferent systems in mediating the response may differ from species to species; the CTZ may have an important role in one species and not in another. Reference may be made to the radio-mimetic drug nitrogen mustard, whose potent emetic action is not fully understood. It may be supposed that the action of the drug is complicated by the secondary effects of cellular damage, comparable with those of X-irradiation: the two agents have much in common in regard to their emetic effects (Borison et al., 1958). Nevertheless, the CTZ is essential for the vomiting response to nitrogen mustard in the dog, since ablation of the zone abolished the response even to a dose of drug many times that normally required to induce vomiting in that species. In the cat, in contrast, the vomiting response to the drug persisted after ablation of the CTZ. It may be noted that, in intact animals, the threshold intravenous dose of nitrogen mustard for vomiting was ten times greater in the cat than in the dog. In the cat, abdominal deafferentation, which was accomplished by transthoracic vagotomy and total sympathectomy, abolished the response. The participation of a further afferent system in the response to nitrogen mustard in the cat was indicated by the observation that the dose-response curve was shifted to a higher dose-level by acute decerebration, and also by the observation that intracarotid injection of the drug evoked emesis at a dose-level too low to be effective by the intravenous route. A facilitatory role of the forebrain was further supported by a protective effect of chronic frontal lobectomy (Borison et al., 1958). An emetic drug may exert an effect through more than one afferent system in a given species, as shown above for nitrogen mustard in the cat. Copper sulphate, which in low oral doses activates receptors of the gastrointestinal tract, may in larger doses activate the CTZ (Borison and Wang, 1953). Morphine acts at the CTZ, but may also activate the vestibular afferent system (Borison and Wang, 1953): in common with other narcotic analgesics, it may also antagonize the effects of emetic stimuli through direct depression of the VC (Costello and Borison, 1977).

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An anomaly may exist in the case of naloxone. McCarthy et al. (1974b) observed that in cats in which the CTZ, the emetic receptor site for opiates, had been destroyed, nevertheless the vomiting response to intraventricular naloxone persisted· The receptor site for naloxone appeared to occupy a ventricular locus between the sub-fornical organ and the area postrema, clearly outside the area normally regarded as the CTZ. It is appropriate to recall, in connection with studies involving ablation of the CTZ in different species, that in the cat the CTZ is a clear-cut entity, morphologically distinct from the dorsal vagal nuclei, while in the dog it is less distinct (Borison and Brizzee, 1951). There is much evidence (Morest, 1967; Gwyn and Leslie, 1978; Gwyn et al., 1979) already described (Chapter 2.1 and 2.3) that certain visceral afférents pass in the immediate vicinity of the CTZ: Lindstrom and Brizzee (1962) pointed out that afférents from a number of peripheral sources may be vulnerable to interruption through surgical procedures in this region. Indeed, these workers observed that, after superficial destruction of the area postrema in a human patient, the vomiting response to oral copper sulphate was lost. Five patients so treated because of intractable vomiting due to brain tumours were relieved of symptoms. All were rendered refractory to apomorphine, confirming that the medullary chemoreceptor function in man resembles that in lower species. The cause of the vomiting in the patients treated by Lindstrom and Brizzee is uncertain. Brain oedema, with a concurrent increase in intracranial pressure, can result from cerebral tumours; the consequent impairment of blood flow results in hypoxia and impedes the removal of metabolites (Hoff and Jellinger, 1967). Wang (1959) in a study of emesis occurring in monkeys exposed to simulated high altitude, was able to show that hypoxia alone is the primary stimulus for emesis under those circumstances. Surgical ablation of the CTZ abolished this response. Thus either hypoxia, or some metabolic products as a result of hypoxia, stimulated the CTZ. It is reasonable to conclude that hypoxia is the most probable primary cause of vomiting in patients with brain tumours. Since Vogt (1954) observed that the area postrema in the dog and the cat contains high concentrations of catecholamines, there has been much research and speculation on the possible role of these substances and associated chemoreceptors in the functioning of the CTZ. The induction of vomiting by intraventricular injection of catecholamines is well known (Borison, 1959; Stewart et al., 1977) and has been referred to previously. Boyd and Cassel (1957) showed that agents causing depletion of catecholamines blocked the emetic effect of apomorphine, and Gaitonde and Joglekar (1975) reported that reserpine, tetrabenazine and syrosingopine similarly blocked the emetic effects of glycosides and ouabain. Certain cells of the area postrema showed catacholamine fluorescence that was augmented when animals were treated with L-DOPA, while nerve cells elsewhere in the brain remained unaffected (Fuxe and Owman, 1965). Torack et al. (1973) defined noradrenergic systems in the area postrema in the cat by correlating the localization of dopamine 3-hydroxylase with observations by electron microscopy, and suggested that the catecholamines function as neurotransmitters of signals received by the tissue as a sensing organ. Jenkins and Lahay (1971) reported that the general anaesthetics diethylether and cyclopropane increase circulating catecholamine levels and are associated with a high incidence of post-operative vomiting, while in contrast halothane and methoxyflurane, which tend to act as adrenergic blocking agents, do not raise catecholamine levels and are associated with a reduced incidence of vomiting. These authors studied the effects of introducing catecholamines at selected CNS sites in the cat. They observed that vomiting followed intraventricular injection of catecholamines with a-stimulating properties (noradrenaline, adrenaline) but that the β-adrenergic agent isopropylnoradrenaline was non-emetic.

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The vomiting due to α-adrenergic agents could be blocked by local a-adrenergic blockade (phentolamine) but not by β-adrenergic blockade (propranolol). Vomiting followed only intraventricular injection of the appropriate agents and was not elicited from other CNS sites: the response from the third ventricle was more rapid than that from the lateral ventricle, which is more distant from the CTZ. The response was central in origin, since no systemic effects were produced. These workers concluded that the central mechanism of vomiting may involve an a-adrenergic mechanism. The recent work of van Dongen (1980), in which the α-noradrenergic agonist clonidine was injected intracerebrally at numerous sites, is of interest in connection with the above observations. This agent elicited vomiting at sites in or near the fourth ventricle, but generally not elsewhere. At clonidine-effective sites the α-noradrenoceptor agonist oxymetazoline was also effective, while the (3-agonist isoprenaline was ineffective. The clonidineinduced vomiting was prevented by the α-noradrenoceptor antagonists yohimbine and piperoxane. At clonidine-effective sites ^-amphetamine, desipramine and surprisingly also morphine and apomorphine were non-emetic, though it should be noted that the amounts used were small. At two out of ten clonidine-effective sites, retching was induced by carbachol. Numerous emetic agents acting at the CTZ, including apomorphine, L-DOPA and hydergine are considered to be dopamine agonists (refs in Lee et al., 1978). Furthermore, it would appear to be established that a range of neuroleptic agents including the phenothiazines, butyrophenones, dibenzodiazepines and dibenzoxazepines, owe both their antipsychotic action and their extrapyramidal and endocrinological side-effects to dopamine antagonism (Snyder, 1978; Clement-Cormier, 1977; Byck, 1978). It has therefore been reasonable to suppose that the antiemetic action shown by these substances is similarly due to blockade of dopamine receptors. Hence it has been suggested that dopamine may play a central role in the mechanism of emesis, with the possibility that excitatory effects at the VC might be mediated by a dopaminergic final common pathway (Borison, 1974). A number of recent observations contradict this hypothesis. Gylys et al. (1974) observed that while the butyrophenone haloperidol, a dopamine antagonist, could block the emetic effects of apomorphine and L-DOPA, it was ineffective against emesis due to morphine. The opiate antagonists naloxone and nalorphine were effective against morphine-induced emesis, but not against that due to apomorphine or L-DOPA. Lee et al. (1978) observed that emesis due to apomorphine, L-DOPA or hydergine was blocked by the neuroleptic agent penfluridol: since small doses of L-DOPA could partly reverse the action of penfluridol against apomorphine, and apomorphine could greatly reduce the protective effect of penfluridol against L-DOPA, these workers could conclude that the antiemetic action of penfluridol is due to dopamine antagonism. This agent was, however, totally ineffective against emesis due to morphine, ouabain, acetylstrophanthidin or nicotine, and only partially blocked that due to adrenaline, emetine or sodium salicylate. It was apparent, therefore, that emetics which act at the CTZ but are not antagonized by penfluridol may act at non-dopaminoceptors. In a later study Lee et al. (1979) concluded that treatment with the dopamine antagonists pimozide and haloperidol was not equivalent to surgical ablation of the CTZ. Both agents were effective against emesis due to apomorphine, L-DOPA or hydergine, but they were ineffective against ouabain or acetylstrophanthidin, which also act principally at the CTZ. Both agents, in higher doses, were moderately effective against reflex vomiting due to copper sulphate, but this might indicate direct depression of the VC. They were ineffective against the emetics veriloid and pilocarpine, which do not act at the CTZ. If emesis elicited through the CTZ was generally dependent on dopaminergic function it would be expected that agents which enhance such function in the central nervous system would have emetic properties. Amphetamine can raise dopamine concentration in the synaptic cleft at dopaminergic synapses either by releasing the neurotransmitter from nerve terminals or by inhibiting its re-

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uptake. The drug increases the turnover-rate of the transmitter in rat striatum, as shown by an increase in the level of 3-methoxytyramine, and this must indicate increased neuronal activity (refs in Di Giulio et al., 1978). Amphetamine is, however, non-emetic. Amantadine, which also releases dopamine, infrequently causes nausea or vomiting in clinical use (Franz, 1975). Bieger et al., (1978) reported that the effective emetic dose of L-DOPA in the cat is six times higher than in the dog, and that L-DOPA emesis is prevented in both species by acute bilateral coagulation of the CTZ. Since carbidopa, a peripheral aromatic amino acid decarboxylase inhibitor abolished the emesis, it could be inferred that the emetic effect is mediated by dopamine in the periphery, acting on the CTZ. This is consistent with the findings in Parkinsonian patients whose condition involves a severe depletion of dopamine in the brain, the result of cell loss in the substantia nigra. In such patients, replacement therapy is hampered since dopamine does not cross the blood-brain barrier. While the precursor L-DOPA does cross the blood-brain barrier, large oral doses are necessary since decarboxylation occurs rapidly in the periphery, and nausea and vomiting are regularly observed. When carbidopa is given together with L-DOPA nausea and vomiting are alleviated and the therapeutic effect is enhanced (Cotzias et al., 1975; Markham et al., 1974) The dopamine agonists apomorphine and bromocriptine similarly alleviate Parkinsonian symptoms, and do not induce emesis if given in combination with domperidone, which blocks peripheral dopamine receptors (Agid et al., 1979; Corsini et al., 1979). It seems clear, from functional as well as from structural considerations (Chapter 2.1) that the CTZ is on the peripheral side of the blood-brain barrier. It is considered that apomorphine may activate dopamine receptors (Gaitonde and Joglekar, 1972; Burkman, 1973; Triggle and Triggle, 1976). The two substances have structural similarities:

apomorphine

dopamine

2-aminotetralin

Most of the behavioural and motor effects of L-DOPA can be mimicked by apomorphine (Sheppard and Brughardt, 1978). Apomorphine in large doses may, however, be antiemetic and may depress respiration (Bieger et al., 1978). Early studies of structure-activity relationships amongst ligands active at dopamine receptors were reviewed by Triggle and Triggle (1976). Subsequently, structure-activity relationships, and the topography of the dopamine receptor, have been studied extensively (Burkman, 1973; Sheppard and Brughardt, 1978; Rusterholz et al., 1979; Philipp et al., 1979; Cannon et al., 1978a,b; Smith et al., 1976; Clement-Cormier et al. 1979; Menon et al., 1976). It may be noted that emetic activity, tested in the dog, resides in certain derivatives of 2-aminotetralin which may be viewed as partial structures of the apomorphine molecule. 2-Dimethylamino-5,6-dihydroxytetrahydronaphthalene was a more potent emetic than apomorphine (Burkman, 1973), while emetic activity was retained even in the absence of hydroxyl substituents, provided that two propyl substituents were present on the nitrogen atom (Rusterholz et al., 1979).

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Much h a s been written on the subject of the non-uniformity of dopamine receptors in the organism; a recent review is that by Kebabian and Calne ( 1 9 7 9 ) . The principal subdivision is that between those dopamine receptors which a r e linked to adenylate cyclase and those which a r e n o t . According to Svendsen (1979) the dopamine receptors in the C T Z of the dog differ from those of the nigroneostriatal dopaminergic system, from which stereotyped behaviour is thought to be provoked, since the sensitivity of the former w a s not increased by prolonged receptor blockade by tefluxitol, while the sensitivity of the latter w a s . Investigations on the action of sulpiride, an antipsychotic agent belonging to the substituted benzamide group (Justin-Besancon et a l . , 1 9 6 7 ) , have been important in regard to the classification of dopamine receptors. This substance exhibits certain antidopaminergic effects similar to those of the phenothiazine neuroleptics, since it is antiemetic, and elevates serum prolactin in m a n ; however, unlike the phenothiazines, sulpiride does not inhibit dopamine-stimulated adenylate cyclase activity either in vitro or in vivo (refs in Theodorou et a l . , 1 9 7 9 ) . H e n c e , a possible inference is that dopamine receptors that a r e independent of adenylate cyclase may be present in the C T Z . Sulpiride, unlike the phenothiazines, has little cataleptic or central depressive action (Theodorou et a l . , 1979) and hence seemingly would not directly depress the V C . According to Hofmann et a l . (1979) sulpiride shows poor penetration into the C N S ; the [ 11 *C]-labelled substance preferentially accumulates in the pituitary gland and the floor of the fourth ventricle, and would therefore act more readily at the CTZ than at other central sites. There i s , however, ample evidence that sulpiride does penetrate to the brain, the (-)-enantiomorph being the biologically active species (Corda et a l . , 1 9 7 9 ) .

O NH2SO

P

Et c H 2 ^ .N

NH^'V^N

OCH, sulpiride

The fact that the dopaminergic ergots, though emetic via the CTZ, are inactive as agonists upon the dopamine receptor which regulates striatal adenylate cyclase (Kebabian and Kebabian, 1978), again argues in favour of the possibility that dopamine receptors that are independent of adenylate cyclase may be present in the CTZ and may be of importance in vomiting. Recently Corda et al. (1979) reported that on systemic or intrastriatal injection dopamine agonists and antagonists such as apomorphine and haloperidol, respectively increase and decrease the cyclic GMP content in cerebellar cortex, while (-)-sulpiride produces a dose-related decrease in cyclic GMP in that tissue. Whether dopamineagonist action at the CTZ might be linked to guanylate cyclase activity is open to speculation. In a biochemical study of various brain tissues of the rabbit, Rudman (1978) found that the biogenic amines histamine, noradrenaline and serotonin failed to elevate cAMP levels in circumventricular organs including the area postrema, though they did so in other brain tissues. Dopamine was not tested. Melanotropic peptides did, however, elevate cAMP levels in area postrema, indicating the presence in that tissue of an adenylate cyclase specifically responsive to melanotropic peptides. In recent observations in mice,

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Zile and Odynets (1980) found that the inhibitory effects of reserpine and haloperidol on brain dopaminergic systems were antagonized by the C-terminal fragment of luliberin, Arg-Pro-Gly-NII2, but were potentiated by the C-terminal fragment of gastrin, Met-Asp-Phe-NH2. The C-terminal tripeptide of oxytocin, Pro-Leu-Gly-NH2, maintained normal levels of dopamine receptor activity. The intact peptide hormones were reported to be without effect on brain dopamine or homovanillic acid levels. It is evident that the problem of the nature of the dopamine receptors in the CNS, and in the CTZ in particular, is a complex one whose elucidation awaits much further study. An added consideration is that dopamine may interact with the α-adrenoceptor (Triggle and Triggle, 1976), whose importance in connection with vomiting was shown by the work of Jenkins and Lahay (1971) and van Dongen (1980) already discussed. Fuxe and Owman (1965) observed nerve cells in the area postrema of the rat which showed 5-hydroxytryptamine fluorescence after treatment with a monoamine oxidase inhibitor and Amin et al. (1954) reported that the area postrema of the dog is rich in 5-hydroxytryptamine, but although it has a neurotransmitter function in the CNS, evidence that would implicate this biogenic amine in vomiting is so far lacking. In man, intravenous injection of 5-hydroxytryptamine may induce nausea amongst a plethora of effects (Douglas, 1975), and intravenous infusion of the metabolic precursor L-5-hydroxytryptophan, with or without carbidopa, evoked vomiting, but the mechanism is obscure (Chadwick et al., 1974; Magnusson and Nielsen-Kudsk, 1979). It may be noted, however, that Woodruff (1971) has suggested the possible existence of a composite dopamine-5hydroxytryptamine receptor. Essman has suggested that 5-HT in glial cells may influence the actions of other neurotransmitters through a calcium-mediated mechanism (1980). The significance of histamine in connection with vomiting is more firmly established. Adam (1966) reported its presence in the area postrema. There is evidence of a neurotransmitter role in mammalian brain (Schwartz et al., 1980). In early work, Hatcher and Weiss (1923) induced emesis in dogs by local application of histamine to the dorsal surface of the medulla, and more recently Bhargava and Dixit (1968) found that intraventricular administration of histamine in dogs induced emesis which was blocked after surgical ablation of the CTZ. Peng and Pi (1967) made a study of the vomiting that occurs in experimental anaphylactic shock in the dog, and explored the mechanism by which vomiting is induced by histamine given intravenously. These workers pointed out that vomiting frequently occurs in drug anaphylaxis in human patients, and that in experimental anaphylactic shock produced with horse serum in the dog and the monkey, vomiting occurs as the initial sign; furthermore, in anaphylactic shock liberation of histamine is known to occur. They demonstrated that in CTZ-ablated dogs, nevertheless vomiting still occurred in shock induced by horse serum. In dogs with an intact CTZ, supradiaphragmatic vagotomy together with sympathectomy from the seventh thoracic to the first sacral ganglia, prevented vomiting in two out of ten cases. However, ablation of the CTZ, combined with sympathectomy and vagotomy, prevented vomiting in six out of seven cases. Intravenous injection of histamine rapidly induced vomiting in normal dogs. Either CTZ ablation, or vagotomy plus sympathectomy, only elevated the emetic threshold of histamine, whereas CTZ ablation combined with vagotomy and sympathectomy prevented the vomiting in three out of five cases. The amount of histamine released in anaphylactic shock in dogs exceeded the ED50 of histamine for vomiting (0.093 mg kg"" 1 ). These workers could therefore conclude that the vomiting of anaphylactic shock is due to histamine release, and that vomiting due to histamine is mediated through three sets of receptors, the CTZ, abdominal visceral receptors responding to abdominal congestion, with afférents in the vagus and sympathetic, and other receptors which are unknown. The fall in

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blood pressure which accompanied the vomiting in anaphylaxis appeared to play only a minor role, since out of six dogs in which a comparable degree of hypotension was induced through haemorrhagic shock, only one responded with vomiting. Peng and Pi observed that, in order to prevent emesis in anaphylactic shock in dogs by CTZ ablation combined with vagotomy and sympathectomy, it was not necessary for ablation of the CTZ to be complete. In some dogs with partial ablation of the CTZ which did not vomit in shock, nevertheless the vomiting response to apomorphine persisted. This observation is consistent with other evidence (vide supra) that receptor activity that is independent of apomorphine (dopamine) receptors can occur at the CTZ. Large parenteral doses of histamine can cause vomiting in man, accompanied by symptoms including a profound hypotension (Douglas, 1975), but doses given by intravenous infusion that were sufficient to stimulate near-maximal gastric acid secretion did not induce nausea, althogh such doses of pentagastrin did (Hunt et al., 1980). The action of injected histamine in man is very brief, since it is rapidly metabolized (Douglas, 1975). It can probably be assumed that in man, as in the dog, histamine may act at multiple sites to induce vomiting; whether hypotension may contribute (Chapter 2.3.2) is uncertain. Schwartz et al. (1980) have stated that both Hi and H2 histamine receptors are involved in the control of cAMP levels in brain, though only H 2 receptors may be linked to adenylate cyclase. In certain nervous tissues, cGMP formation is stimulated by histamine, mediated by Hi receptors. Rudman (1978) (vide supra) found that histamine failed to elevate cAMP levels in rabbit area postrema. Bhargara et al. (1976) found, in the dog, that the H x antagonist mepyramine and the H2 antagonists burimamide and metiamide given intraventricularly could protect against emesis due to histamine given by the same route, and hence they could conclude that both Hi and H 2 receptors are present in the CTZ and are involved in histamine-induced emesis. The PD50 values of intraventricular mepyramine, burimamide and metiamide against the 100% emetic dose of histamine (3.0 mg intraventricularly) were approximately 200yg, 20ug and 20ug respectively. A four-fold increase in the 100% emetic dose of histamine was required to overcome the effect of the equipotent PD50 doses of burimamide or mepyramine, hence it is possible that Hi and H 2 receptors have an equal significance in the emetic response. Intraventricular burimamide gave only partial protection against intravenous histamine suggesting, in agreement with the observation of Peng and Pi (1967), that histamine may also act through peripheral receptors. Burimamide was ineffective against emesis from oral copper sulphate or intravenous apomorphine, indicating that the H2 antagonist did not depress the VC in non-specific fashion, and further confirming the independence of dopamine and histamine receptors in the CTZ. The emetic action of clonidine, an agonist at α-adrenergic receptors, on intracerebroventricular injection (van Dongen, 1980) has already been referred to. Audigier et al. (1976) found that clonidine also stimulates brain H 2 receptors, an action prevented by metiamide: whether metiamide influences the emetic action of clonidine has not been investigated. A third histamine receptor subtype (H 3 ) has been postulated (Chand et al., 1979); whether this might have any significance in connection with vomiting is not yet known. It has been suggested that the vomiting in pregnancy and in motion sickness (Bhargava, 1974) and that due to radiation exposure (Ellinger, 1951) may be mediated through the action of histamine. These questions will be considered in the appropriate chapters in this review. It mav be noted here that Soûles et al., (1980), in a recent review of the vomiting of pregnancy, have concluded that an endocrine aetiology, though persisting as a popular theory, remains unproved despite exhaustive study; rather, a psychiatric aetiology is suggested. The

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hypothesis of Hook (1974) in regard to the vomiting of pregnancy was referred to in the introduction· Any possibility of direct cholinergic action at the CTZ, in the species tested, would appear to be eliminated by observations that acetylcholine, physostigmine and pilocarpine failed to induce vomiting by topical application to the medulla (Borison and Wang, 1953)· Gwyn and Wolstencroft (1968) obtained strong cholinesterase staining in the area subpostrema, but not in the area postrema itself. However, acetylcholine, physostigmine and pilocarpine evoked prompt vomiting in unanaesthetized man and in other species by the intraventricular route; these responses could be abolished by atropine given parenterally or intraventricularly· Borison and Wang (1953) suggested that this action of atropine is indicative that the drug may block transmission in an excitatory pathway from the hypothalamus to the VC, perhaps at interneural synapses· In a subsequent study in the cat, Borison et al. (1956) determined that the central emetic action of pilocarpine is mediated by an important central component, dependent on the integrity of the frontal lobe of the cerebrum. It may be recalled that van Dongen (1980) observed retching, but not vomiting, in response to carbachol administered at certain sites in or near the fourth ventricle in the cat. It has been postulated that cholinergic activity may be of importance in the genesis of motion sickness, and this will be considered in the appropriate chapter. From the foregoing discussion, certain tentative conclusions may be drawn regarding the nature of the receptor populations of the CTZ. It is convenient to summarize these conclusions, confining attention to receptors for the "established" neurotransmitter substances. Thus for the induction of vomiting, the α-adrenoceptor, but not the (3-, is important. The dopamine receptor which is not linked to adenylate cyclase may be more important than that which is linked to the enzyme. Both types of histamine receptor, Hi and H 2 , are involved in the response to histamine. Apparently, cholinoceptors have no significant role in the CTZ, and any role of serotonin receptors is not proved. Although certain ligands may activate more than one type of receptor it is probable, on the evidence, that vomiting can be induced through the activation, independently, of the populations of α-adreno-, dopamino- and histaminoceptors present in the CTZ. Studies reported in the recent literature indicate that discrete receptors responding to endogenous substances other than the neurotransmitter amines are associated with the CTZ and may be opérant in the induction of vomiting via this chemosensory organ. Special interest attaches to certain peptides and amino acids which are putative neurohormones or neurotransmitters. It is accepted that morphine acts to induce vomiting at the CTZ (Borison and Wang, 1953; Stewart et al., 1976) and that this action is independent of α-adreno- (Stewart et al., 1976) or dopaminoceptors (Gylys et al., 1974). The response is abolished by naloxone (Stewart et al., 1976). Several types of opiate receptor may exist in the CNS: morphine and the benzomorphan derivative, ketocyclazocine, have been considered to be prototype agonists at the so-called y and κ.receptors, (Cowan et al., 1976). Ketocyclazocine did not cause emesis in the dog (Pickworth and Sharpe, 1979). Costello and Borison described a dual action of morphine in connection with vomiting. While the drug can induce emesis, it is also capable non-selectively of blocking the emetic activity of numerous substances which utilize a multiplicity of inputs to the VC. These authors concluded that inhibitory opiate receptors exist on neurons associated with the VC, and that the effect of opiates is determined by interactions with counteracting receptor populations; chemoreceptive emetic receptors of the CTZ on the one hand, and synaptic antiemetic receptors on the other (1977). A number of endogenous peptides, which appear to serve as natural ligands for opiate receptors, have been demonstrated in brain, pituitary, human cerebrospinal fluid and human blood (refs in Pert, 1976)·

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The pentapeptides methionine-enkephalin (Tyr-Gly-Gly-Phe-Met) and leucine-enkephalin (Tyr-Gly-Gly-Phe-Leu) produce several opiate-like effects in vivo, but their actions show quantitative and qualitative differences (Cowan et al., 1976). Methionine-enkephalin, like morphine, caused emesis when injected intracerebroventricularly, an effect prevented by pretreatment with naloxone (Clark, 1977). Whether leucine-enkephalin has this emetic effect does not appear to have been recorded. It is clear that receptors exist in the CTZ, capable of responding to endogenous opioid peptides to induce vomiting, and that these receptors are distinct from aminergic receptors. Also it is probable, from the work of Costello and Borison, that receptors exist on neurons associated with the VC which respond to endogenous opioid peptides and mediate an inhibitory effect. In this connection, it is of interest that Klee et al. (1976) observed that methionine- and leucine-enkephalins, like morphine and related narcotics, can inhibit adenylate cyclase in tissue homogenates, a receptor-mediated effect blocked by naloxone; these authors expressed the view that these neurohormones can be expected to inhibit adenylate cyclase activity of neurons with opiate receptors and thereby suppress the effects of other neurotransmitters which activate the enzyme. Siggins (1979) has reviewed the probable modulatory action of enkephalins on excitatory synaptic transmission, for example that due to glutamate. One may speculate that natural opioid peptides might have a role in the regulation of vomiting, through shifts in the levels of these substances in the neighbourhood of the VC. The emetic action of naloxone when given alone (McCarthy et al., 1974b) and the ability of the drug to enhance the emetic action of centrally-administered adrenaline (Stewart et al., 1976) could be attributed to blockade of such inhibitory control. It may be relevant that McCarthy et al., ( 1974b) observed that the emetic response to intraventricular naloxone did not depend on the integrity of the CTZ. Mention has already been made of the observation that melanotropic peptides may interact with receptors in cells of the area postrema of the rabbit (Rudman, 1978). It was observed that periodic hypersécrétion of ACTH was accompanied by vomiting that could be blocked by chlorpromazine, but the mechanism is obscure (Sato et al., 1980). Since numerous peptide substances, first identified in the gut, have also been identified in areas of the CNS (brain-gut peptides) and are regarded as putative neurotransmitters (Bloom and Polak, 1978), the question arises as to whether chemoreceptors for such peptides might occur in cells of the CTZ. Although methionine-enkephalin can induce vomiting via the CTZ, the possibility that other brain-gut peptides, such as substance P (Nicoll et al., 1980) might have a similar action, remains unexplored. Kaneko and Uchiyama (1979) found that the peptide hormone glucagon induced emesis in pigeons which was not prevented by bilateral vagotomy, suggesting participation of a central trigger zone. The emesis was strongly suppressed by chlorpromazine, which might suggest the intervention of a dopaminergic mechanism, although it should be recognized that the phenothiazine may directly depress the VC. In a recent review on the significance of the excitatory or neurotoxic amino acids Watkins (1978) has stated that most cells of the mammalian CNS can be assumed to have receptors for glutamate and aspartate, irrespective of the presence of cholino-, amino-, peptido- or other types of receptor on the same cell. It was found in early work that glutamate and aspartate excited cholinoceptive and noncholinoceptive cells alike, and it has become clear that the amino acids are similarly effective on the relatively minor groups of cells which are excited also by noradrenaline, serotonin, histamine, substance P and enkephalins (Watkins, 1978). Studies of excitatory amino acids stemmed from early observations that glutamic and aspartic acids were the only protein amino acids which induced vomiting in dogs when given intravenously (Madden et al., 1945; Unna and Howe, 1945). The D forms were equipotent with the L forms in producing emesis (Watkins, 1978). In a study of the occurrence of nausea and vomiting in patients following

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intravenous administration of amino acid mixtures Levey et al. (1949) found that vomiting occurred in more than half the subjects when serum glutamate reached a level of 12-15 mg 100ml" 1 . A recent study showed that, in rhesus monkeys given monosodium glutamate (1-4 g kg""1) orally, peak values occurred in the serum 1-2 hr after dosing; although not precisely correlated with serum glutamate values, vomiting tended to occur at the time of the observed glutamate peaks (Heywood et al., 1978). L-Aspartic acid has been found to induce nausea in human patients (Kavach et al., 1979). In early work, Roth et al. (1946) found that nembutal or noradrenaline given intravenously increased the tolerance of dogs to intravenously infused glutamate, hence they suggested that a sedative might be of value clinically to counter the emesis which might result from the infusion of protein hydrolysates or amino acid mixtures. It might be supposed that nembutal, like other general sedatives, would directly depress the VC. It is noteworthy that the D and L forms of allylglycine, which prevents the conversion of glutamic acid to γ-aminobutyric acid (GABA) through inhibition of the enzyme glutamic acid decarboxlylase (GAD), showed emetic action in a primate (Meldrum et al., 1979). The GAD inhibitor monomethylhydrazine is also emetic (Sterman and Kovalesky, 1979). Whether, in these instances, the emetic effects are due to accumulation of glutamate, or to depletion of GABA, an inhibitory neurotransmitter (Kruk and Pycock, 1979), is uncertain. Although glutamic acid is the most abundant amino acid in mammalian brain, it is considered that its location is intracellular and that its excitatory or neurotoxic actions upon neurons are exerted when the anion is present in the extracellular compartment. The CNS is protected to some extent from exogenous glutamate by the blood-brain barrier, and extracellular accumulation of endogenous stores is prevented by rapid mechanisms of uptake, probably mainly into glial cells. The neurotoxic effects are believed to occur as a result of a persistent, abnormally high degree of excitation of neurons by the anion (Olney, 1978). Since they lie outside the blood-brain barrier, certain circumventricular organs, including the area postrema, are prone to neurotoxic damage from glutamate given systemically (Olney and Price, 1978). Olney et al., (1977) established that glutamate administered intravenously induces lesions in the area postrema of mice, and Olney and Rhee (1978) made similar findings in the rhesus monkey. These workers put forward the hypothesis that since, apparently, large doses of glutamate can excite area postrema neurons to death, then lower doses should stimulate such neurons sufficiently to trigger vomiting. Hence it is reasonable to add to the range of amino- and peptido- emetic receptors of the CTZ, already specified, receptors for the excitatory amino acids. Apart from glutamic and aspartic acids themselves, a wide range of synthetic amino acids structurally related to these have been shown to possess neuroexcitatory properties, in some instances with greater potency, for example kainic acid (KA) and N_-methyl-D-aspartic acid (D-NMA). Several sulphur-containing amino acids are strongly excitatory, notably D-homocysteic acid. Certain of these sulphur-containing substances, for example cysteine-sulphinic and cysteic acids, have been detected in the CNS and the possibility that they may be involved in synaptic excitation has been pointed out. This might suggest a possible significance in connection with vomiting in certain circumstances. At least two types of receptor for excitatory amino acids have been proposed to exist in the CNS; it is believed that KA and D-NMA may act at different receptors. It is of interest that certain chemical compounds which are antagonists at these receptors are known (Watkins, 1978). The emetic side effects of prostanoids when these substances are used to induce abortion was referred to in the Introduction. Eiler and Paddleford (1979) found in dogs that a rapid emesis of short duration occurred after injection of prostaglandin F2Qt, and they suggested that this agent may become the preferred

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emetic for use in dogs in cases of poisoning, or when emptying of the stomach is required before anaesthesia· Kaul et al. (1978) found that prochlorperazine and hydroxyzine significantly reduced vomiting following the use of PGF2a in women; they suggested that since PGF2a ^ a s a direct spasmogenic effect on the smooth muscle of the gut, its emetic effect might be mediated through afférents from this source. In that case, the antiemetic agents would be acting, presumably, through depression of the VC. Lippes and Hurd (1975) observed that chlorpromazine suppressed emesis due to prostaglandin E2. These workers expressed the view that chlorpromazine generally provides little or no antagonism against vomiting induced by drugs acting locally on the GI tract. This would imply an emetic effect of the prostanoid via the CTZ. There is as yet, however, no direct evidence that the CTZ contains receptors responding to prostanoids. Note should again be taken of the observation that activity of neurons of the CTZ was stimulated by centrally-administered ATP (Borison et al., 1975). From the above discussion it is apparent that the CTZ contains discrete populations of receptors that can be activated by a diversity of endogenous substances, and it is unlikely that all of these have been identified. It may be supposed that the liberation of such substances in abnormal amounts into the blood or cerebrospinal fluid may account, at least in part, for the emetic effects of cytotoxic insults to the organism such as radiation injury or the administration of antineoplastic drugs.

2.3.4.

Labyrinth

In several species, including man, an intact labyrinth has been shown to be indispensible for the occurrence of sickness in response to certain kinds of motion. Vomiting from this cause is considered to be essentially the same as vomiting from other stimuli (Reason and Brand, 1975). An extensive literature has accumulated on the topic of motion sickness and, as mentioned in the Introduction, important reviews are those by Money (1970), and by Reason and Brand (1975). Largely from these sources, the main features are outlined here; also included are items from more recent literature. It has been recognized that motion sickness is the normal response of a healthy animal to exposure to abnormal forms of motion. Since the response lacks survival value, it remains an unexplained anomaly. While susceptibility is an individual characteristic, all individuals will succumb if the stimulus is of adequate strength and duration. The dog and man are roughly equally prone. In man, the cardinal signs and symptoms are pallor, cold sweating, nausea and vomiting, although vomiting in the absence of nausea has been reported; less consistent phenomena are excessive salivation, drowsiness and depression. Pallor and sweating, unlike nausea and vomiting, are autonomie in origin. Head discomfort, occurring in a minority of exposed subjects, may be distinct from the nausea syndrome. Gastric relaxation precedes vomiting, but is not necessarily coincident with the sensation of nausea. Visceral afférents play no important role in the vomiting from motion sickness. Furthermore, afférents from higher centres play no essential role; in decerebrate animals the capacity to vomit in response to swinging motion is unimpaired, and motion sickness with vomiting was observed in a decorticate man. In normal human subjects, however, the cerebrum can exert a powerful influence for either suppression or facilitation of the process; pre-occupation with mental tasks can markedly reduce the incidence of sickness, and placebo effects in trials of remedies can be very large, whereas on the other hand, concentration upon the subjective sensations during exposure to motion can markedly increase the incidence of sickness.

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Susceptibility to motion sickness is absent in labyrinthine-defective humans, and in mammals that have suffered bilateral labyrinthectomy or section of the eighth cranial nerves. The morphology of the afferent pathway is described by Reason and Brand (1975). Afferent impulses from the labyrinth are conducted to the co-ordinating centre of the vestibular system, the vestibular nuclei; thence neuronal connections are made with a number of CNS structures, including the nuclei of the third, fourth and sixth cranial nerves, the spinal cord and the cerebellum (see Fig. 3).

Cerebrum

III, IV, VI Nuclei (reflex eye movements)

Hypothalamus (autonomie responses e.g. sweating, pallor, salivation)

Labyrinthine receptors

Efferents (To muscles concerned in vomiting and G.I.T.)

Fig. 3.

Diagram of principal structures involved in motion sickness syndrome. Reproduced from Reason and Brand (1975), Motion Sickness, Academic Press, N.Y.

It was shown that, in regard to motion sickness, the cerebellar structures essentially involved are the nodulus and uvula, since extirpation of these in the dog conferred immunity to the effects of swinging motion. Such dogs vomited normally in response to apomorphine. Pathways proceed to the cerebrum and to the hypothalamus, which governs the autonomie components of the syndrome. The excitatory pathway to the medullary vomiting centre apparently passes via the CTZ; ablation of this structure in the dog was found to abolish the emetic response to motion. In recent work, Brizzee et al. (1980) determined the effect of destruction by thermal cautery of the area postrema, bilaterally, in eight squirrel monkeys; in five of the animals ability to vomit after combined rotation and sinusoidal vertical motion was lost. In the remaining three monkeys the response was diminished; at autopsy these were found to have some area postrema tissue remaining. These workers regard the CTZ as synonymous with the area

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J. H. Barnes

postrema. Roy and Brizzee (1979) were able to establish a conditioned food aversion in squirrel monkeys that were exposed to a motion stimulus that generally was insufficient to provoke frank emesis. This suggested that while the emetic response is mediated by the area postrema, the malaise, nausea and autonomie reactions may be mediated by structures above the level of the caudal medulla. The nature of the mediatory role of the area postrema in motion sickness remains an unsolved problem. At an early date Chinn and Smith (1955) made the suggestion that its role might be related to a chemical substance liberated in motion which triggers CTZ receptors. Brizzee et al. (1980) state that the only known fibre connections of the area postrema are those with the nucleus solitarius, as described bv Morest (Chapter 2.1); it is unknown whether fibre connections with the vestibular nuclei or cerebellar structures exist. Many types of motion, vehicular and experimental, can lead to motion sickness and these have been described at length (Money, 1970; Reason and Brand, 1975). Simple vertical oscillations can be effective provided that the frequency does not exceed 0.55 Hz; the optimum frequency is of the order of 0.24 Hz. Swinging motion is most effective when the radius is about 15 ft and the frequency 0.23 Hz. In most forms of motion, head movements relative to the body contribute to the nauseogenic effect; fixing of the head in vehicular motion dramatically reduces the incidence of motion sickness. In a subject that is rotated, especially effective is the stimulus resulting from tilting movements of the head about some axis other than that of body rotation (Coriolis acceleration); this stimulus, produced, for example, when a slow-rotation room (SRR) is employed, has been much used experimentally. Aso, spit rotation about a horizontal axis is a particularly potent stimulus. The common characteristic of all effective motions is that the head is subjected to varying acceleration, whether linear or angular. Constant accelerations are.ineffective (Money, 1970). 0THanlon and McCauley (1974) have made a detailed study in human subjects of the incidence of motion sickness as a function of the frequency and acceleration of vertical sinusoidal motion and have derived a mathematical model from the data. Incidence was found to be greatest at a frequency of 0.167 Hz. For all wave frequencies, incidence increased as a monotonie function of the acceleration level. These workers pointed out that the model has potential applications for the design of desirable vehicle ride characteristics. Even moderate accelerations at a frequency near 0.2 Hz should be avoided, and an engineering strategy to "smooth out" a ride at the expense of high frequencies should be considered cautiously. Reason and Brand (1975) indicated that in laboratory experiments with human subjects, a pre-vomiting endpoint, usually nausea, is preferable to frank vomiting. The onset of sweating has also been used in motion sickness rating procedures (McClure and Fregly, 1972). Recently Wiker et al. (1979) have reviewed the use of a point scale of the severity of pre-vomiting symptoms in such work and have demonstrated its application in an examination of the influence of hull design and steaming direction on sickness occurring in sea-going craft. Steaming into the primary swell was most productive of sickness. It would clearly be desirable to be able to predict from laboratory tests the susceptibility to air-sickness of candidates in flight training programmes from economic viewpoint. Lentz and Guedry (1977) have made a retrospective comparison of the suitability of three different laboratory tests on aviation personnel in distinguishing airsick individuals from those less prone. While such a distinction could be made, evaluation of the data suggested that several tests would be advantageous over a single test in any effort to predict air-sickness susceptibility. Eversmann and co-workers (1978) have noted that although psychological, clinical and physiological tests of individual susceptibility have been applied, endorcrinological factors have not so far been

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used for this purpose. These workers found that the stress of Coriolis stimulation provoked significant and reproducible increases from the basal serum levels of antidiuretic hormone (ADH), of growth hormone, of prolactin and of cortisol, whereas luteinizing hormone levels did not change significantly· The stimulation of hormone secretion induced by different degrees of motion sickness appeared to correlate with motion sickness severity. ADH secretion was the most sensitive indicator. Earlier studies indicated that ADH secretion is influenced by the functional state of the vestibular system. The stress of frank vomiting could lead to a 21-fold increase of serum ADH levels. Optokinetic stimulation also provoked secretion of stress hormones, but to a less extent. The data indicated that hormone secretion depends on the individual susceptibility to motion sickness. Thus it was concluded that determination of hormone secretion may prove helpful in predicting motion sickness susceptibility. It would appear that the symptoms of motion sickness experienced by certain astronauts in a condition of weightlessness are contingent upon head movements; vertigo, nausea and frank vomiting have occurred (Reason and Brand, 1975). In recent papers, Schneider and Crosby (1980a,b,c) have drawn attention to certain special features of "space sickness"; unformed visual hallucinations (flashes of light), formed visual hallucinations (distorted images) and sensations of inversion in space have been experienced. Schneider and Crosby observed that these effects are similar to those experienced by certain patients with expanding intracranial lesions, whose symptomatology is referable to the temporoparietooccipital cortex of the brain. This suggested the possibility that the symptoms experienced in space might be due to cortical hypoxia as a result of compression or spasm of the posterior cerebral artery brought about by acceleration from the thrust of rocket-motors, but this seems highly speculative. Gurovskiy et al. (1975) have referred to a possible role in space sickness of a redistribution of blood in a state of weightlessness. In conditions of hypoxia, vestibular tolerance to Coriolis acceleration is decreased. Experience in cosmonaut training showed that subjects showing stable haemodynamic indices during vestibular tests tolerated space flight well. The role of visual stimuli in motion sickness has been discussed in detail (Money, 1970; Reason and Brand, 1975). In some circumstances sickness is promoted by vision and in others it is suppressed. When visual motion information is in agreement with that from the vestibular system and the non-vestibular proprioceptors sickness is reduced, but when the visual information is in conflict with that from other sensory modalities sickness is promoted. Thus, as is well-known, in vehicular motion a visual earth reference is beneficial. On the other hand, movement of the visual field in the absence of corresponding body motion can cause motion sickness. Labyrinthine-defective individuals are not affected by movements of the visual field. It was suggested that moving visual fields initiate conditioned activity in the vestibular centres (Money, 1970). From Dichgaus and Brandt (1973), pseudo-Coriolis effects and optokinetic motion sickness are elicited by inclinations of the head out of the axis of rotation of a circular visual surround which moves, giving the illusion of self-rotation. The tilt sensation and the symptoms so produced are like the true Coriolis effects which arise from similar head movements when the body is actually rotating, but are smaller in magnitude. It appeared that two components are necessary to elicit pseudo-Coriolis effects; one is a central equivalent of vestibular excitation mediated by visual motion information, the other is vestibular input generated by the head movement. It was suggested that in order to avoid motion sickness, ample peripheral vision of the external surround should be provided; alternatively projection of a comparable moving pattern might be helpful, though the latter remained to be proved. Subsequently Guedry (1978) has put forward the hypothesis, with experimental support, that optokinetic stimulation in a given head plane modifies activity in the vestibular nuclei as

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though the semicircular canals in that plane had been stimulated. The disturbance caused by dissonant inputs from the semicircular canals and otoliths can be modified by interaction with those optokinetic inputs to yield a pattern that will be synergistic and neither disorientating nor nauseogenic. Guedry supposed that not the vestibular nuclei alone, but also vestibular-cerebellar interactions may be involved. The phenomenon of adaptation, a progressive reduction in the response to continued nauseogenic motion stimuli, has received much attention (Money, 1970; Reason and Brand, 1975). In this context the term does not describe a diminished receptor response, in which sense it is normally used, but rather describes a central process possibly akin to learning. Habituation to the motion of a ship is well known. Such habituation may not be transferable on changing from one vessel to another; similarly, repeated exposure to swinging motion affords no protection against air-sickness. In some circumstances, however, positive transfer of adaptation has been found to occur. Thus, repeated exposure of flight trainees to large Coriolis accelerations on several days in the laboratory conferred protection against air-sickness. Russian cosmonauts have been given "vestibular training", but with unknown results (Money, 1970). Dobie (1974) described his methods of treating air-sickness in flight training, employing psychotherapy in combination with adaptation to cross-coupled angular (Coriolis) accelerations on a rotating-tilting table; a "cure-rate" of 86% was achieved. More recently Graybiel and Knepton (1978), also working with flight trainees that were subject to air-sickness, employed a schedule of exposure to rotation in a single direction accompanied by head movements. Transfer of adaptation to the unpractised direction of rotation was found to occur, and also transfer to flight maneouvres. Five out of eight candidates regained flight status, but in two candidates the rate of acquisition of adaptation was unsatisfactorily slow. Antimotion sickness drugs were used with advantage during the adaptation process. Because of the acquisition of adaptation, if exposure to a nauseogenic motion stimulus is sufficiently prolonged, then cessation of the motion produces a recurrence of the disturbance elicited during the initial period of exposure. Such an effect is seen in "mal de débarquement". The after-effects are related causally and quantitatively to the degree of adaptation aquired. When the initial effects have a directional sign, the after-effects have the opposite sign. When head movements are made in a stationary environment immediately following prolonged rotation with Coriolis acceleration symptoms are produced, even extending to vomiting; these effects occur only if the head movements are identical with those made in acquisition of the adaptation (Reason and Brand, 1975). Graybiel and Lackner (1980) employed a rotation and sudden-stop test to determine the rates of acquisition and decay of adaptation in human subjects. Subjects were exposed to motion, firstly with eyes covered, in a rotating chair in a striped cylindrical enclosure under standard conditions for 30 sec, then decelerated to a stop within 1.5 sec and kept at rest for 30 sec while symptoms were recorded. The procedure was repeated until a preselected endpoint (slight nausea) was reached, or 20 stops had been made. If the endpoint was not reached, similar testing continued without the blindfold. If the endpoint was still not reached, the direction of rotation was reversed. The subject was awarded a score based on the amount of motion stress required. Subjects were assessed four times with intervals of three days between tests. The first test gave a poor indication, but the second provided a satisfactory ranking of motion sickness susceptibility and the results of the four sessions gave an indication of the rates of acquision and decay of adaptation. It was found that low susceptibility was often not a good indicator of the rates of acquisition or decay of adaptation. At sea or in flight training, good retention of adaptation is more important than is a rapid rate of acquisition; but in brief space missions rapid acquisition is all-important.

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Any theory of motion sickness, to be satisfactory, must explain not only the essential nature of the stimulus, but also must account for the observed differences in susceptibility between individuals and furthermore it must explain the phenomena of adaptation and the after-effects of adaptation which have been discussed. Early theories which laid emphasis upon overstimulation of spatial senses have not survived since they could not explain certain observations; for example, that vertical oscillations at high frequency are less nauseogenic than those at low frequency· Theories which put forward sensory conflict as the basis of motion sickness have had greater currency. In early versions, it was considered that the primary conflict was between the vestibular and visual senses (an inter-modality conflict) but it was later realised that discord can also exist between signals from the otolith organs and those from the semicircular canals (an intra-modality conflict) in conditions such as weightlessness in space and in rotation of the body round an earth-horizontal axis. Since an intact vestibular apparatus is necessary for motion sickness to occur, it is apparent that conflict between visual input and that from the non-vestibular proprioceptors is in itself insufficient to cause symptoms. Thé theories of motion sickness and the evidence have been discussed in detail by Reason and Brand (1975), who have propounded a comprehensive theory based upon sensory conflict which is perhaps best understood from their own account. The main thesis is that "all situations which provoke motion sickness are characterized by a condition of sensory rearrangement in which the motion signals transmitted by the eyes, the vestibular system and the nonvestibular proprioceptors are at variance not only with one another, but also - and this is the crucial factor - with what is expected on the basis of past experience or fexposure history1". Many types of sensory rearrangement are likely to be involved: six basic nauseogenic conflict situations are described by Reason and Brand. While the notion of sensory rearrangement seeks to describe the nature of the stimulus, its corollary the "neural mismatch" hypothesis, seeks to explain the central mechanism of motion sickness and of the phenomenon of adaptation and its consequence, the reappearance of symptoms on cessation of the stimulus. Postulated are (1) a neural store which retains an impression of spatial sensory inputs and (2) a comparator unit which compares current sensory input with that in the neural store. Where current and the stored impressions differ, a "mismatch signal" is generated which, when vestibular input is involved (either directly, or indirectly as in visually-induced sickness), is directed into reflex pathways by which motion sickness is generated. With continued exposure to an abnormal environment the neural store is progressively updated so that the mismatch signal is gradually eliminated. On a return to normal conditions a mismatch again occurs so that symptoms can again be produced, waning as readaptation progresses. Since traces of normal experience remain stored throughout, readaptation is more rapid than adaptation. Reason and Brand (1975) point out that neurophysiological evidence from recent sources supports the probability that neuronal systems appropriate to these functions exist in the CNS. No theory explains why motion sickness takes the form it does; why the end result is not, for example, sneezing rather than vomiting. Attention may be drawn to the hypothesis of Treisman (1977), mentioned in the Introduction. Individual susceptibility is determined by two factors, receptivity and adaptability; no systematic relationship exists between the two. These factors and their measurement in human subjects have been discussed at length (Reason and Brand, 1975). In terms of the neural mismatch hypothesis, receptivity is determined by the size of the postulated mismatch signal generated at a given level of stimulation, while adaptability is determined by the rate at which the neural store is updated. In practice, it has been found that adaptability is the more important factor in determining susceptibility. Retentiveness of adaptation is also an important factor. These findings have been used to develop a procedure for screening out high-risk individuals (Reason and Brand,

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1975)· Information as to the impact of motion sickness on performance is sparse· In certain military operations, it might be an important factor. It is believed that in a motion-sick individual motivation plays an important part in determining performance· It would seem that the act of vomiting must inevitably impair performance (Money, 1970; Reason and Brand, 1975). Disorientation of pilots associated with head movements during turning maneouvres in aircraft (Coriolis effect) at low altitudes may have precipitated a series of accidents (Guedry and Benson, 1978). Certain operations in space have had to be delayed or aborted because of sickness of key personnel. However, in experimental studies, exposure to motion (vertical accelerator or slow-rotation room), whether causing sickness or not, seems to have had surprisingly little effect on performance task scores (Reason and Brand, 1975). Certain measures which can be effective in preventing or ameliorating the effects of motion have already been referred to. Habituation to the form of motion concerned is clearly of special value. Postural measures can be very helpful. In subjects exposed to swinging motion, those adopting a supine position were found to show one-fifth of the incidence of motion sickness that occurred in those retaining a sitting posture. With swinging motion and seated subjects with eyes covered, restriction of head movement reduced the incidence of sickness to one sixth. A visual earth reference when the head was free to move was found to reduce motion sickness incidence by a large factor. Concentration upon mental tasks during motion, so that the amount of attention that could be devoted to subjective sensations was reduced, was markedly beneficial (Money, 1970). Nevertheless, the use of drugs against motion sickness has been investigated extensively. As mentioned in the Introduction, this subject has been reviewed by Wood et al. (1965a,b), by Brand and Perry (1966), by Money (1970), by Reason and Brand (1975) and by Wood (1979). Reviewers have noted that field trials of drug efficacy have often given conflicting results. A given drug may appear to be very effective in one trial but less so in another. These discrepancies are hardly surprising in view of the number of variable factors in such trials (Brand and Perry, 1966). Since in field trials the stimulus is not wellcontrolled, the effectiveness of a drug may be assessed by comparing the incidence of symptoms (usually vomiting) in a group of subjects given the drug with that in a placebo group, within a fixed time. In different trials, the incidence of vomiting in the placebo group may vary from below 20% to over 90%. The index of protection, or percentage of susceptible persons protected, is given by (% vomiting in placebo group) - (% vomiting in treated group) % vomiting in placebo group

χ

1Π~

Values of 50-75 have been found for the better drugs tested (Money, 1970; Brand and Perry, 1966). In laboratory studies (eg SRR) where the stimulus can be controlled, the amount of stimulus (eg the number of head movements at a fixed frequency) required to reach a designated criterion of sickness, can be recorded (Money, 1970). As previously mentioned, in laboratory studies nausea is preferable to frank vomiting as a criterion of sickness. In all drug tests, the timing of administration in relation to the motion exposure is an important consideration, since different drugs may reach an optimum of activity at different intervals after administration, and they may be effective for different periods of time. As an illustration, promethazine in a dose of 35 mg was found to be significantly less active than hyoscine (0.7 mg) when the drugs were given

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orally 45 min before motion lasting 1 hr in a life-raft; however, promethazine was later shown to be effective in a dose of 25 mg, given two or three times per day orally during a 48 hr experiment at sea. Although hyoscine (0.7 mg) was highly effective when given 1 hr before a short period of motion, it was ineffective when given orally two or three times per day during a long exposure to motion (Brand and Perry, 1966). Drugs should, ideally be tested in accordance with a knowledge of the variation of the blood levels with time, but it appears that often, little regarding the blood levels is known. Also, it is unfortunate that the dose-response relationships for motion sickness drugs in common use have not yet been properly investigated, except in the case of hyoscine (Brand and Perry, 1966). Since all the drugs used hitherto have undesirable side effects, which usually include sedation, such information would be valuable in deciding upon dosages that are effective while giving an acceptable level of side effects.

Table 2.

Dosages and Duration of Action of Antimotion Sickness Drugs

Drug(s)

Hyoscine + dexamphetamine

Dose (mg)

0.3-0.6 + 5-10

Durât ion of Action (hr)

Condition

6

Severe

Promethazine + ephedrine

25 + 25

12

Severe

Hyoscine (1-scopolamine)

0.3-0.6

4

Severe

Promethazine

25

12

Severe

Dimenhydrinate

50

6

Moderate

Cyclizine

50

4

Mild

Meclozine

50

6

Mild

Reproduced with permission from Wood (1979) Drugs 17, 471-479

Despite the difficulties experienced in testing, a small group of drugs has been identified as effective against motion sickness and these have been regularly used (see Table 2 ) . These include 2 r n y o s c i n e (scopolamine) and the antihistamines promethazine, cyclizine, meclozine and diphenhydramine. Also active are ^-amphetamine and the barbiturate V12 (ethyl (3-methylallylthiobarbituric acid). Hyoscine as the hydrobromide would appear to be the most effective single drug when the motion is of short duration; oral doses of 0.1-0.6 mg are active, and 0.3 mg is almost as effective as 0.6 mg, with less troublesome side effects. The side effects include drowsiness, blurred vision and dry mouth, but performance is, apparently, little affected by the drug (Money, 1970). However, it was reported recently that hyoscine impaired learning and memory in certain circumstances. (Liljequist and Mattila, 1979). Hyoscine has normally been administered orally, but McCauley et al. (1979) have tested a system for the controlled, transdermal administration ot the drug, in subjects that were exposed to vertical oscillations in the laboratory; by this means continuous antinauseant protection could be provided for up to 72 hr, with reduced side effects.

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In SRR tests the sympathomimetic agents amphetamine (10 or 20 mg) and ephedrine (50 mg) were protective against motion sickness. Amphetamine (20 mg) was as effective as hyoscine (0.6 mg). Oral combinations of hyoscine with either amphetamine or ephedrine were highly effective. The combination of hyoscine (0.3 mg) with amphetamine (5 mg) was superior to hyoscine (0.6 mg) given alone (Reason and Brand, 1975). This combination has been recommended as the preparation of choice for use in brief exposures to motion: it may be taken by mouth 1 hr before exposure and is effective for up to 3 hr (Money, 1979). It has been employed successfully against space sickness (Reason and Brand, 1975), but not always reliably (J.M. Talbot, personal communication). For the antihistamines, as already mentioned, details of the dose-response and response-time relationships are not available (Reason and Brand, 1975). Promethazine, in a dose of 25 mg, is the most effective of this group against motion sickness. The effect is prolonged but sedation is marked (Wood, 1979). In SRR tests oral combinations of promethazine (25 mg) with amphetamine (10 mg) or with ephedrine (50 mg) were highly effective (Reason and Brand, 1975). Diphenhydramine (50 mg) has a long duration of action but is sedative. Cyclizine (50 mg) has few side effects and may be used for short-term mild exposure (Wood, (1979). Meclozine may also be used for short exposures (Money, 1970). From Wood (1979), diphenhydramine (50 mg), cyclizine (50 mg) or meclozine (50 mg), orally, should be sufficient to counter the effects of motion likely to be experienced during civilian air or sea travel. During prolonged exposure doses may be given three times a day. Under more severe conditions promethazine (25 mg) with or without ephedrine (25 mg) may be used. Under very severe conditions hyoscine (0.3 to 0.6 mg) with or without amphetamine (5 to 10 mg) may be required. Promethazine or hyoscine may be given therapeutically, after motion sickness has developed, by the intra-muscular route; both produce drowsiness. Graybiel and Knepton (1977) have observed that the responses of individuals to antiemetics vary widely, and that it is therefore difficult to find an ideal drug for everyone. McMurray (1973) pointed out that sedation is the major disadvantage of antiemetics in current use. Metoclopramide (Chapter 4) a peripherally-acting drug which increases gastric motility, was given intramuscularly, in a dosage of 10 mg, to 50 subjects who complained of symptoms of seasickness. Of these, 88% had acceptable relief from symptoms, without sedation. Those successfully treated did not request further treatment within 24 hr. The drug was, however, less active than promethazine (25 mg) by the same route. In a recent paper Towse (1980) has reviewed studies of the drug cinnarizine, a noncompetitive antagonist of histamine, noradrenaline, nicotine and angiotensin. In the guinea pig, cinnarizine (10 mg kg - 1 , i.p.) was superior to diphenhydramine (25 mg kg"""1), meclozine (10 mg kg ) or cyclizine (10 mg k g - 1 ) in reducing the duration and intensity of caloric-induced nystagmus. In human subjects, the duration of post-rotational nystagmus and post-rotational turning sensation were both reduced by cinnarizine. Clinically, the drug was found to be of value in the treatment of vestibular vertigo from various causes. In SRR tests cinnarizine had some effect against motion sickness but was much less effective than hyoscine-amphetamine. However, in an open study involving 500 yachtsmen cinnarizine gave excellent results against seasickness, and was considered by the subjects to be superior to hyoscine or promethazine. The optimum regime was 15 mg given orally three times per day. 20% of the subjects reported drowsiness as a side effect of the drug. A theory of motion sickness was proposed by Wood and Graybiel (1970, 1972) based on the pharmacological properties of drugs known to be effective against motion sickness. These workers pointed out that effective drugs fall into two categories, those having central sympathomimetic action, and those having central anticholinergic action. Thus ephedrine and amphetamine are protective, while

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agents having sympatholytic effects such as phenoxybenzamine, thiethylperazine and prochlorperazine are either inactive, or, in high dosage, increase susceptibility to motion sickness· Hyoscine is strongly protective, while the antihistamines having anticholinergic properties are also protective: of these promethazine, which has the most pronounced anticholinergic action, is the most potent. The combination of hyoscine with amphetamine is synergistic and the combination of promethazine with ephedrine shows additive effect. In addition, intracarotid injection of the cholinesterase inhibitor diisopropylfluorophosphonate (DFP) in animals was found to provoke a vestibular effect resulting in forced circling movements, indicating that acetylcholine is of importance in vestibular function. It was therefore suggested that there may be competing neural systems in the brain stem involved in motion sickness, one cholinergic and the other most probably mediated by noradrenaline. There is evidence that some neurons in the vestibular nuclei and in the adjacent reticular system are cholinergic; adjacent to or intermingled with these are others which are moradrenergic (Wood and Graybiel, 1970, 1972). It was proposed that, in exposure to an unusual force environment, there would be an unusual level of activity in the vestibular nuclei which could radiate through the adjacent reticular areas to activate the vomiting centre. Vomiting of motion sickness could therefore be due to an anatomical accident, that the vomiting centre and the vestibular system are both involved with adjacent neurons of the reticular activating system. It was suggested that the noradrenergic system would activate neural systems in order to offset the effects on the vomiting centre. Motion sickness would result when the build-up of cholinergic activity became sufficient to outweigh the noradrenergic activity. Jaju et al. (1970) obtained evidence as to the site of action of hyoscine and atropine in controlling motion sickness. It had been shown by previous workers that vestibular neurons gave an excitatory response to electrophoretically applied acetylcholine, an effect blocked by intravenous atropine . The electrical activity of neurons of the medial vestibular nucleus was recorded in a cat preparation. The spontaneous activity of these neurons was found to be enhanced by electrical stimulation of one of the vestibular nerve branches or by stimulation of the labyrinth by angular or linear acceleration. Spontaneous firing, and firing caused by motion or by electrical stimulation, were suppressed by atropine or hyoscine given intravenously. The results suggested that atropine and scopolamine were able to depress the neuronal excitability of the vestibular nuclear complex and it was considered that this might explain the action of the drugs against motion sickness. It was suggested that the vestibular nuclear synapse might be an important site of cholinergic transmission. Similar studies were conducted with the antihistamine diphenhydramine, which has anticholinergic properties. The results suggested a similar mode and locus of action for this drug. It was considered that the action of diphenhydramine against motion sickness is unlikely to be due to histamine antagonism, since no correlation appears between the antihistaminic potency of drugs and their ability to prevent motion sickness (Jaju and Wang, 1971). In a later study with the same experimental system Kirsten and Schoener (1973) showed that dihydro-3-eryfhroidine given intravenously was without effect on the discharge rate of vestibular uniLs, hence the cholinergic synapses on vestibular neurons cannot be nicotinically mediated. Also, since intravenous procaine was without effect on vestibular firing, a non-specific local anaesthetic mechanism cannot account for the action of antimotion sickness drugs. Since atropine methyl nitrate and hyoscine methyl bromide, both antimuscarinic agents which do not cross the blood-brain barrier, were without effect on vestibular discharge, then it appears that the action of antimotion sickness drugs is not due to a depressant action at the peripheral end-organs. Also from this study, evidence was adduced that the inhibition of vestibular neurons following intravenous administration of muscarinic blocking agents might not, as previously thought, be due to a direct effect on the

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vestibular synapse, but rather might be the result of a modified input from the reticular formation. Brandt et al. (1974) observed that both diphenhydramine and hyoscine were effective in preventing nausea and vomiting from optokinetic pseudo-Coriolis effects (evoked by. head movements during an illusory body rotation), just as they were in preventing those symptoms from true Coriolis effects. This supports the concept that there is a powerful convergence of visual information on to vestibular structures, and indicates that the final pathway to the vomiting centres begins in the vestibular nuclei for both optokinetic and vestibular motion sickness. In studies with the drug cyclizine, Reicke (1976) made the interesting finding that, although the drug was effective against the nausea induced by Coriolis stimulation in man, it had no significant effect, compared with placebo, on either the amplitude and frequency of the per-rotary nystagmus, on the duration of the post-rotatory nystagmus, or on the rotational after-sensation following a sudden stop. The dose of cyclizine used was 50 mg, given 1 hr before the motion. In these experiments, the sensations of tilting and vertigo were unaffected by the drug. In contrast, diphenydramine was found to reduce post-rotatory nystagmus. Reicke took these results to mean that cyclizine, unlike diphenhydramine, is without effect on the vestibular system and exerts its effect at the vomiting centre. Cyclizine was reported to be effective against radiation emesis (Fochem, 1964); whether this is due to histamine antagonism, or to central depression, or to some other action, is not known (Chapter 3 ) . It should be noted that chlorpromazine, which may depress the reticular vomiting centre and is effective against radioemesis (Chapter 3 ) , is ineffective against motion sickness. Brand and Perry (1966) and Reason and Brand (1975) have considered in detail the usefulness of various screening tests in the search for effective antimotion sickness drugs. There is no doubt that the search for such agents would have been greatly facilitated, had a reliable screening test been available. It would appear that the only reliable test of a drug is a properly conducted field trial in man. Nevertheless laboratory methods with human subjects, using Coriolis stimulation and a suitable endpoint would appear to be of value, provided that drug dosage and timing of administration are fully considered. Tests of vestibular function in man involving measurement of calorically-induced nystagmus, post-rotatory sensation times or post-rotatory nystagmus would seem to be promising. Of tests with animals, it is unlikely that tests based on drug-inducing vomiting can be of significance. Nor would tests employing swinging as a stimulus seem to be useful. However, tests of vestibular function in certain species (eg. caloric irrigation tests in guinea pigs) may offer useful information. Use of the adversive syndrome (forced circling movements following intracarotid injection of DFP) may be of value in so far as the antimotion sickness agents have anticholinergic properties. Hamaun et al. (1977) have expressed doubts as to the value of the post-rotatory nystagmus test in the rabbit. They found, in rabbits that were rotated for 10 sec, that the duration of post-rotatory nystagmus was shortened by diphenhydramine (dimenhydrinate, 2 mg kg~]) but was prolonged by thiethylperazine (1 mg kg"1) or dehydrobenzperidol (1 mg k g - 1 ) . Thus agents having similar effects clinically behaved differently in the test. Finally, attention should be drawn to a recent review of the field of space motion sickness by Talbot (1983), in which the multidisciplinary problems are identified and means of working towards their solution are indicated.

2.3.5.

Supramedullary Sites of the CNS

It is evident that the medullary vomiting mechanism can function

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independently of connections with higher levels of the central nervous system. In decerebrate animals, vomiting still occurs in response to intravenous apomorphine, although the threshold may be slightly raised, which suggests that the cerebrum can exert a facilitatory function. Vomiting, with its associated activities, occurs undiminished in response to motion in the decerebrate dog (Borison and Wang, 1953; Reason and Brand, 1975). Nevertheless, it was observed at an early date that electrical stimulation of areas of the hypothalamus and thalamus in the unanaesthetized cat evoked reactions which occasionally included vomiting. Such vomiting occurred at an interval after stimulation, in contrast to the immediate, projectile vomiting response to electrical stimulation of the medulla. It was therefore concluded that vomiting can be initiated at supramedullary neuronal sites from which impulses are transmitted in a descending direction; furthermore, it was supposed that these sites can subliminally affect the excitability of the medullary vomiting centre (Borison and Wang, 1953). A number of descending pathways are known by which motor activity organised at lower levels of the brain stem may be directly influenced by forebrain areas (Bieger et al., 1978). Robinson and Mishkin (1968) have observed the responses to electrical stimulation of numerous forebrain sites in the monkey. The highest probabilities for initiating a vomiting response were found in the amygdala, ventralis anterior, anterior perforated area and hippocampus. Lower probabilities were found in the fornix, septum, putamen and midline thalamus. It may be recalled that vomiting induced in the cat by nitrogen mustard was impaired by decerebration and more especially by frontal lobectomy, which suggested that the forebrain serves to facilitate the peripherally initiated vomiting reflex (Borison et al., 1958). Although acetylcholine, physostigmine and pilocarpine failed to induce vomiting by topical application to the medulla, these drugs evoked prompt vomiting in unanaesthetized man and other species when given intraventricularly. These responses were abolished by atropine, probably at synapses on a descending, excitatory pathway from the hypothalamus to the reticular vomiting centres (Borison and Wang, 1953) (Chapter 2.3.3). The phenomenon of adaptation to motion is an example of a partly cerebral mechanism that powerfully influences the development of sickness. The influence of psychological factors on nausea and vomiting has been referred to on several occasions in this review. Large placebo effects have been observed in trials of antiemetic substances against emesis due to motion (Chapter 2.4) or radiation exposure (Chapter 3 ) . Voluntary mental activity can markedly influence the development of motion sickness (Chapter 2.4). Unpleasant odours, and odours associated with previous bouts of sickness have been observed to promote motion sickness effectively (Money, 1970). It is of interest that a psychiatric aetiology of the vomiting of pregnancy has been suggested (Soûles et al., 1980). Hyperemesis gravidarum has been treated by hypnosis (Fuchs et al., 1980). Vomiting as a conditioned response was reported to be rare; rather, conditioned salivation was observed in a number of cases (Borison and Wang, 1953; Money, 1970). Pretreatment nausea occurring during a course of cancer chemotherapy has been considered to be a classical conditioned response (Nesse et al., 1980). Money (1970) concluded that although psychological influences (suggestion, concurrent activity and conditioning) are demonstrably operative in regard to vomiting, still physical and physiological factors outweigh them in practical importance. It may be supposed that the various afferent systems considered in this Chapter, which determine the level of excitation of the reticular vomiting centre, can act in an additive manner to induce emesis, and there is some evidence to support this supposition. It is apparent that input from higher centres can influence vomiting primarily induced by any other afferent pathway. Normal head movements would seem to be important for the occurrence of emesis from treatment with apomorphine; it is probable that under normal circumstances the labyrinth maintains a tonic influence on the CTZ. It has been observed that

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emesis following radiation exposure is influenced by posture and movement. Motion which is insufficiently severe to cause emesis may do so when an emetic agent has been administered (Money, 1970),