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Hindbrain morphology is compared in a variety of animals representing species that vomit and those that do not. Special attention is given to the nucleus of the tractus solitarius (NTS) and its synaptic connections with surrounding structures. The role of the area postrema is examined from the standpoints of containing the chemoreceptor trigger zone (CTZ) for vomiting, of its functional relationship to the blood-brain barrier, and of its significance as part of the circumventricular organ system. A survey is made of the manifold behavioral contributions of NTS to cardiovascular and respiratory regulation, appetite control, arousal, water balance, and digestive and neuroendocrine functions. An overview is presented of neurochemical distribution in the brain stem with respect to aminergic, cholinergic, and peptidergic substances. Finally, causes and prevention of vomiting are discussed in light of the above considerations.

1 In cats anaesthetized with pentobarbitone and vagotomized, observations were made on the phrenic nerve action potential and the diaphragm electromyogram (EMG) at constant end-tidal Pco(2). Arterial blood pressure was stabilized by intravenous infusions of noradrenaline.2 Intravenous administration of saxitoxin (STX) initially abolished respiratory activity in the EMG and caused a slowing of oscillation in the central phrenic neurogram. Additional STX produced apneustic phrenic discharges followed by a progressive loss of nerve action potentials.3 The inspiratory centre in the medulla oblongata was stimulated electrically to evoke a sustained phrenic nerve discharge. STX, given intravenously, resulted in the elimination of spontaneous nerve activity without interfering with the evoked response.4 The cephalic intravascular infusion of STX into a carotid or vertebral artery depressed spontaneous respiratory activity while sparing EMG activity evoked by electrical stimulation of the intact phrenic nerve.5 Spontaneous respiratory discharge in the phrenic nerve was eliminated by smaller doses of STX administered intra-arterially than were required intravenously. In addition, onset of and recovery from neural silence occurred faster following intra-arterial injection of STX.6 Depressant effects on arterial blood pressure coincided with those on respiration when STX was given intra-arterially.7 An electrophysiological assay on frog sartorius muscle was used to measure STX in the cerebrospinal fluid. Levels of STX detected were proportional to amounts of the toxin infused intra-arterially.8 It is concluded that STX exchanges rapidly between blood and brain to bring about central depression and this adds to its peripheral paralytic actions.

The comprehensive emetic response to xenobiotics can be quantified by monitoring the physiological forces which effectuate vomiting. A unique sequence of thoracic pressure pulses, generated by the somatic muscles of ventilation, can be measured by means of a central venous catheter. This unambiguous emetic endpoint is used to record emetic latency, repetitions and duration of action, all on an established time base and dependent of stomach content. Deslanoside (160 micrograms/kg) produced emesis in 15 cats beginning in 4.4 +/- 1.9 min (mean +/- S.D.). Subsequent emetic episodes were related in time in a log-linear but biphasic manner. Cisplatin (7.5 mg/kg) had an emetic latency of 71 +/- 18 mn in 7 cats. Additional events also had a long-linear temporal relationship for up to 400 min. This quantified emetic profile of cisplatin served as a measure for assessing antiemetic activity of N-metyllevonantradol (Pfizer), nabilone (Lilly) and prochlorperazine. The cannabinoids all evinced dose dependent antiemetic activity in terms of either complete protection, or increased latency to the first emetic episode and reduced number of episodes in those animals not completely protected. By comparison prochlorperazine afforded only minimal protection.

1 In cats anaesthetized with pentobarbitone, saxitoxin and, on a few occasions, tetrodotoxin were injected into a lateral cerebral ventricle or into the subarachnoid space of the lower brain stem. Observations were made on frequency and tidal volume of breathing, on CO(2) responsiveness and on electrical responsiveness of the respiratory centre. Effects on the blood pressure were observed simultaneously.2 A single large dose of toxin, e.g., 250 ng, produced within minutes apneustic breathing and a rise in blood pressure which were converted rapidly to respiratory failure and hypotension. In contrast, repeated small doses, e.g., 25 ng, yielded only progressive slowing of the respiration together with circulatory hypotension. Bulbar depression was produced as effectively by subarachnoid injection as by intraventricular injection of the toxins. Onset of action was detectable within seconds.3 Slowing of the respiration occurred independently of change in tidal volume and whether or not the vagus nerves were cut. The reduction in breathing frequency is attributed to direct toxin-induced depression of the central respiratory oscillator.4 Steady-state measurements of tidal volume at controlled levels of alveolar CO(2) pressure in intermediate stages of respiratory depression showed that the toxins produced an increase in CO(2) stimulation threshold as well as a reduction in gain of CO(2) responsiveness, whether or not the vagus nerves were cut. Carotid arterial chemoreceptor reactivity to O(2) was demonstrable when central sensitivity to CO(2) was depressed. These effects are attributed to a direct influence of the toxins upon the brainstem CO(2)-tidal volume controller.5 Responsiveness of the medullary inspiratory centre to electrical stimulation persisted after the failure of spontaneous breathing was caused by the toxins. Conversely, restitution of electrical responsiveness preceded the reappearance of spontaneous respiratory activity in the recovery phase of toxic depression. Circulatory effects paralleled the changes in respiratory behaviour.6 On the basis of the relatively prompt and discrete alterations in the central respiratory and circulatory control mechanisms produced by saxitoxin and tetrodotoxin placed in the cerebrospinal fluid, it is concluded that the agents rapidly penetrated to deep target loci in the lower brain stem.

1 In cats anaesthetized with pentobarbitone, observations were made on respiration, spontaneous and evoked diaphragmatic electromyograms, blood pressure, heart rate, indirectly-induced contractions of the anterior tibialis muscle and nictitating membrane, and electrical excitability of the inspiratory centre in the medulla oblongata.2Gymnodinium breve toxin (GBTX) was administered intravenously, intra-arterially to the brain, and intracerebroventricularly. Physiological effects were recorded while alveolar P(CO) (2) was controlled at a constant level except when changes in gas tension were made in order to measure CO(2)-ventilatory responsiveness.3 Adequate doses of GBTX given intravenously by bolus injection elicited a non-tachyphylactic reflex response triad of apnoea, hypotension and bradycardia mediated by the vagus nerves independently of arterial baroreceptor and chemoreceptor innervation.4 After vagotomy, additional amounts of GBTX (i.v.) resulted in apneustic breathing, hypertension and tachycardia. The cardiovascular effects were abolished by ganglionic blockade with hexamethonium.5 Smaller doses of GBTX were required intra-arterially and intracerebroventricularly than by the intravenous route of injection to produce respiratory irregularity and cardiovascular hyperactivity.6 Evoked motor responses, electrical excitability of the medulla oblongata and CO(2)-ventilatory responsiveness were largely spared even though GBTX caused marked disturbances in respiratory rhythmicity and cardiovascular functions.7 It is concluded that GBTX acts reflexly on vagally innervated receptors to evoke a Bezold-Jarisch effect but that the toxin further acts centrally to cause irregular breathholding and hypertension with tachycardia, leading ultimately to respiratory and circulatory failure.

1. In cats anaesthetized with pentobarbitone, the fluid spaces in and around the brain stem were perfused from the third ventricle to the foramen magnum with artificial cerebrospinal fluid (c.s.f.) flowing usually at the rate of 5 ml/minute. Test solutions were substituted for the artificial c.s.f. without switching artifact for periods varying from 5 to 60 seconds. Observations were made on respiratory excursions, end-expiratory% CO(2) and arterial blood pressure.2. Perfusion with sucrose solution equiosmolar with the c.s.f. produced no respiratory or cardiovascular response. Replacement of sodium with potassium (60 to 133 mM) resulted in a prompt but mild respiratory stimulation and a delayed fall in blood pressure associated with a slowing of the heart beat. Replacement of sodium with magnesium (40 to 131 mM) resulted in a late prolonged apneustic depression of breathing and in an early but slight reduction in blood pressure.3. Procaine (1 to 50 mg/ml) elicited a respiratory response similar to that of excess magnesium; however, an initial rise in blood pressure to as high as 200 mmHg was evoked with procaine. Nicotine (0.05 to 0.5 mg/ml) produced an immediate brief bradypnea followed by a vigorous and slowly reversing hyperpnea accompanied most often by a fall in blood pressure. Tachyphylaxis was observed in the response to nicotine. Noradrenaline (0.001 and 0.1 mg/ml) did not produce any effect, and it did not alter the responses elicited by procaine and nicotine given by perfusion either simultaneous with or subsequent to the noradrenaline. Acetylcholine (0.5 mg/ml) produced weak transient respiratory stimulation and a small fluctuation in blood pressure which disappeared in repeated tests. Methacholine (1 mg/ml) caused a brief hyperpnea and a fall in blood pressure both of which were abolished after atropine (0.2 mg) was injected into the third ventricle. Pilocarpine (10 mg/ml) elicited no change in respiration or blood pressure. Respiratory and cardiovascular effects produced by strychnine (1 mg/ml) were attributable non-specifically to convulsive movements of the animal. Ethamivan (1 mg/ml) produced a single deep breath and a slowly reversing rise in blood pressure. Cyanide (0.5 mg/ml) barely stimulated the respiration but it produced a long lasting rise in blood pressure. Ethyl alcohol (0.1 ml/ml) elicited brisk though brief respiratory stimulation and a short lasting fall in blood pressure.4. It was shown that the effects of procaine and nicotine were not qualitatively altered when the perfusion effluent was collected through a ventral craniotomy instead of the cisterna magna.