Antitussive effects of two specific kappa-opioid agonists, U-50,488H and U-62,066E, in rats

The effects of highly selective agonists of kappa-opioid receptors, namely U-50,488H and U-62,066E, on the capsaicin-induced cough reflex in rats were studied. Intracisternal (i.cist.) injection of U-50,488H and of U-62,066E significantly decreased the number of coughs in a dose-dependent manner. The antitussive potency of i.cist. injection of these two kappa-opioid agonists was similar to that of morphine. Intraperitoneal (i.p.) injection of U-50,488H and of U-62,066E also decreased the number of coughs, again in a dose-dependent manner. The antitussive effects of U-50,488H and U-62,066E were blocked by norbinaltorphimine, an antagonist of kappa-opioid receptors. Methysergide, administered i.cist. (3 nmol), antagonized the antitussive effects of U-50,488H and U-62,066E. However, ketanserin had no effect on the antitussive effects of these kappa-opioid agonists. These data suggest that U-50,488H and U-62,066E exert their antitussive effect on rats through stimulation of kappa-opioid receptors. Furthermore, with respect to the antitussive effects of kappa-opioid agonists, the system that involves 5-HT1 receptors may be more important than the system that involves 5-HT2 receptors.