Vagal-induced vomiting in decerebrate cat is not suppressed by specific 5-HT3 receptor antagonists

Cancer therapy with cytotoxic drugs such as cisplatin or cyclophosphamide is usually associated with violent crisis of vomiting. Recently, it was shown that 5-HT3 receptor antagonists block cisplatin-induced vomiting but the mechanisms and their sites of action remain unknown. We tested the hypothesis that these agents act on structures within the central nervous system by evaluating the effectiveness of vagal stimulation in eliciting fictive vomiting in decerebrate, paralyzed and ventilated cats before and after administration of such agents. Fictive vomiting was defined as a series of large bursts of synchronous activity in the phrenic and abdominal (expiratory) nerves (retching) followed by a burst in which the abdominal activity was prolonged (expulsion). The latency and number of these co-activations were measured before and after intravenous administration of three 5-HT3 receptor antagonists (GR 38032F (Ondansetron). Zacopride, and BRL 43694A (Granisetron]. All compounds, administered at doses of 1 and 2 mg/kg failed to block vomiting behaviour in 100% and 68% of trials, respectively. Nor did their administration affect the latency and number of co-activations. We conclude that intravenous administration of 5-HT3 receptor antagonists do not act centrally on either the brainstem neuronal network known as the "vomiting center" or related neuronal structures. Our results suggest that the anti-emetic effect of 5-HT3 receptor antagonists in cisplatin-induced vomiting is mediated peripherally rather than centrally.