Pharmac. Ther. Vol. 39, pp. 367 to 371, 1988 0163-7258/88 $0.00+0.50 Printed in Great Britain. All rights reserved Copyright © 1988 Pergamon Press plc Symposium Editors: J. F. WEISS and M. G. SIMlC MECHANISMS OF RADIATION-INDUCED EMESIS IN THE DOG DAVID O. CARPENTER, DEAN B. BRIGGS and NORMAN L. STROMINGER Department of Anatomy, Albany Medical College, 47 New Scotland Avenue, Albany, New York 12208, U.S.A. 1. INTRODUCTION Nausea and vomiting are characteristic and unpleasant side effects of exposure to ionizing radiation in humans and some experimental animals. About 50% of humans exposed to 1.8 Gy will experience these symptoms (Lushbaugh, 1974), which occur with a latency of about 1-2 hr and last for several hours. At doses of 3.0 Gy almost 100% will vomit (Gerstener, 1960). These side effects can be very debilitating and often become the limiting factor in a patient's acceptance of radiation therapy. Thus, finding a pharmacologic way to prevent these symptoms is important, and an understanding of the mechanisms involved is critical to the development of a rational prophylaxis. Our present understanding of the neural pathways involved in nausea and vomiting comes to a great degree from work done in the 1950s by Wang, Borison and Brizzee, summarized in Wang's book (1980) and a recent review by Barnes (1984). Emesis can be triggered through several pathways, all of which act ultimately to excite a stereotypic pattern of somatic muscle contractions, particularly abdominal muscles and diaphragm. While the early studies suggested that there was a motor emetic 'center' (Wang and Borison, 1952), recent evidence indicates that a confined center probably does not exist (Miller and Wilson, 1983), and it is much more likely that, instead, there is a brain stem central pattern generator, i.e. a network of interconnected neurons, probably including at least neurons in the nucleus tractus solitarius, which when activated trigger the sequential excitation of the various motorneurons (Carpenter, 1988). This central pattern generator can be activated directly by gastrointestinal (mainly vagal) afferents responding to irritation or by excitatory input from the area postrema, one of the circumventricular organs that lies outside of the blood-brain barrier and is positioned to respond to circulating drugs and toxins. The area postrema, or the portion thereof that serves this function, was called the "chemoceptive trigger zone" (CTZ) by Borison and Brizzee (1951). In addition to drug-induced emesis, several other types of emesis have been reported to be dependent upon the integrity of the area postrema, although not always without some disagreement between studies. The dependence upon the area postrema is important, for such dependence strongly suggests that that particular form of emesis acts through an agent released into the blood stream or cerebrospinal fluid (CSF). Radiation-induced emesis has been found to be dependent upon the area postrema in monkeys (Brizzee, 1956) and dogs (Brizzee et al., 1958; Harding et al., 1985) but not in cats (Borison, 1957). Motion-induced emesis has also been reported to be dependent upon the area postrema in dogs (Wang and Chinn, 1954) and monkeys (Brizzee et al., 1980) but not in cats (Borison, 1985). Our laboratory has been involved in studies of the emetic reflex, using the' dog as an experimental model. Species variations are a major problem in this field. The dog is closest to humans in sensitivity to emetic drugs, radiation and motion (Borison et al., 1981) and is probably the best animal model available. We have used electrophysiological recordings from neurons of the area postrema to characterize the receptors for circulating substances, and have found that a variety of neurotransmitters, peptides and hormones will excite these neurons (Carpenter et al., 1983; Briggs and Carpenter, 1986). Furthermore, there is a good correlation between the presence of excitatory receptors on these neurons and emesis being elicited by the 367