PRODUCTION OF HYPOTHERMIA IN THE GUINEA-PIG BY A KAPPA-AGONIST OPIOID ALONE AND IN COMBINATION WITH CHLORPROMAZINE

In rats, kappa opioids decrease body temperature and the combination of a selective kappa agonist with chlorpromazine induces a profound hypothermia. Because of the greater density of kappa-opioid receptors and increased ratio of kappa to mu in the guinea pig, the actions of these drugs on body temperature were compared in this species. Groups of young adult, male Hartley guinea pigs were injected SC with trans-3,4-dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide methanesulfonate, hydrate (U50,488H; 20-80 mg/kg) and chlorpromazine (2.5-5 mg/kg), either alone or in combination. Rectal temperatures were measured over a 5-h period. U50,488H produced a dose-related decrease in temperature, with a mean maximum drop of approximately 7-degrees-C. The maximum decrease with chlorpromazine was approximately 1.6-degrees-C. When doses at the lower end of the range for each drug were given together, the combined effect was greater than that expected from the individual drugs. Both the peak effect and the duration of the hypothermia appeared to be potentiated. At the highest dose combination only an additive effect was seen. Compared to the rat, the hypothermic effect of the kappa agonist alone is much greater in the guinea pig. The potentiation between the two drugs, however, is greater in the rat.