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.
Lehmann
A
A
Preclinical R&D, Gastrointestinal Pharmacology, Mölndal, Sweden.
Kärrberg
L
L
D000818:Animals; D002945:Cisplatin / Q000037:antagonists & inhibitors*; D003915:Dextromethorphan / Q000494:pharmacology*; D004639:Emetics / Q000037:antagonists & inhibitors*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005289:Ferrets; D017829:Granisetron / Q000494:pharmacology; D008297:Male; D008559:Memantine / Q000494:pharmacology*; D010875:Pipecolic Acids / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D002945:Cisplatin; D003915:Dextromethorphan; D004639:Emetics; D018691:Excitatory Amino Acid Antagonists; D017829:Granisetron; D008559:Memantine; D010875:Pipecolic Acids; D016194:Receptors, N-Methyl-D-Aspartate; C053672:selfotel