Effects of N-methyl-D-aspartate receptor antagonists on cisplatin-induced emesis in the ferret

Glutamate may be a key transmitter in the emetic reflex arc. The present investigation focussed on the involvement of the NMDA subtype of glutamate receptors in cisplatin-induced emesis. Ferrets were injected with cisplatin (10 mg/kg i.v.) and either of the non-competitive NMDA receptor antagonists dextromethorphan or memantine, or the competitive receptor antagonist CGS 19755. In order to determine whether there is a synergism between NMDA blockers and 5-HT3 receptor antagonists, a submaximal dose of granisetron (0.05 mg/kg) was given alone or in combination with either dextromethorphan or memantine. The latency for the onset of emesis as well as the total number of vomits and retches over 3 hr were determined. In controls, the latency for emesis was 73 +/- 6 min and the total number of vomits and retches 143 +/- 17. The corresponding figures for animals treated with dextromethorphan, 10 and 20 mg/kg, were 89 +/- 19 min (p > 0.05) and 50 +/- 17 (p = 0.008), and 113 +/- 18 min (p > 0.05) and 22 +/- 9 (p = 0.004), respectively. At 10 mg/kg, dextromethorphan failed to enhance the antiemetic effect of granisetron which by itself provided 90% inhibition. While memantine (2.5 or 5.0 mg/kg) did not have an effect per se, it tended to reduce the antiemetic effect of granisetron. CGS 19755 (10 mg/kg) provided a partial protection against cisplatin-induced emesis (latency: 111 +/- 23, number of vomits and retches 30 +/- 11). None of the NMDA receptor antagonists was free of behavioural effects (e.g. some sedation) at antiemetic doses. It is concluded that NMDA receptor antagonists may afford protection against cisplatin-induced emesis but the specificity of this effect is uncertain since it may relate to general CNS depression.