ABSTRACT
T. ENDOl•*, M. MINAMI \ M. HIRAFUJI \ N. HAMAUE1 and S. H. PARVEZ2 1 Department of Pharmacology, Health Sciences University of Hokkaido, I shikar i-Tobetsu, Hokkaido 061-0293, Japan
2 Alfred Fressard Institute of Neuroscience, CNRS UPR 2212-Bat 5, Chateau CNRS 91190, GifSur Yvette, France
Abstract-The ferret (Mustela putorius furo), a carnivore weighting 1-1.5 kg, is highly valued as a small animal model for determining the emetic activity of cytotoxic drugs. Because of its sensitivity to emetic stimuli, the ferret is now being used routinely for testing novel cytotoxic drugs and antiemetic agents. In our laboratory, ferrets were evaluated on their behavioral changes, pathological changes and pharmacological responses to cytotoxic drug-induced emesis. Cisplatin-induced emesis in ferrets was inhibited by 5-HT3 receptor antagonists in a dose dependent manner. 5-HT levels in the area postrema and in the ileum were increased by cytotoxic agents. Both abdominal vagotomy and ondansetron, a 5-HT3 receptor antagonist, remarkably inhibited cisplatin-induced emesis and cisplatin-induced increase in 5-HT levels in the area postrema. The cisplatin-induced increase of the ileal 5-HT levels, however, was not inhibited by vagotomy or ondansetron. Furthermore, compared with intraperitoneal administration, oral administration of ondansetron blocked cyclophosphamideinduced emesis more effectively and significantly. These results suggest that cytotoxic drugs induce emesis mainly through actions on the gastrointestinal tract. Cytotoxic drugs may cause 5-HT release from the enterochromaffin (EC) cells of the intestinal mucosa to stimulate 5-HT3 receptors on the afferent vagal fibers. Stimulation from the afferent vagal nerves appear to produce an increase in 5-HT levels in the area postrema. The increased 5-HT levels in the area postrema might trigger the emetic response induced by cytotoxic agents. In this review, we also discuss abdominal afferent vagus nerve activity and 5-HT release from EC cells using data from our laboratory.
