Subcutaneous or i.c.v. administration of U50,488, a highly selective kappa opioid agonist, resulted in a dose-and time-dependent anticonvulsant action in rats. The anticonvulsant effect was seizure-specific; thus, U50,488 protected against supramaximal electroshock seizures but failed to raise the threshold of flurothyl-induced convulsions. The ED50 for s.c. U50,488 was 8.6 mg/kg, with a duration of action longer than 8 hr. In contrast, the ED50 for i.c.v. U50,488 was 103.8 micrograms, lasting approximately 1 hr. The anticonvulsant effect of U50,488 was partially antagonized by high (10.0 mg/kg), but not low (1.0 mg/kg), doses of s.c. administered naloxone. Results indicate that U50,488 is an efficacious, long-acting anticonvulsant against supramaximal, but not chemical threshold, seizures in rats. Furthermore, the results with naloxone suggest that this effect of U50,488 is mediated by non-mu (probably kappa) binding sites. This structurally novel nonpeptide opioid may offer new insights into the development of therapeutically effective agents in the treatment of grand mal or partial epilepsies.