The effect of NG-monomethyl-L-arginine (NMMA), an inhibitor of nitric oxide synthase, on the development of tolerance to the analgesic and hypothermic actions of U-50,488H, a highly selective kappa-opiate agonist, was determined in the rat. Male Sprague-Dawley rats were rendered tolerant to the pharmacological actions of U-50,488H by twice daily intraperitoneal injections of the drug (25 mg/kg) for 4 days. To determine the effect of NMMA on tolerance to U-50,488H, NMMA was administered 10 min prior to each injection of U-50,488H. Multiple injections of U-50,488H resulted in the development of tolerance to its analgesic and hypothermic actions. NMMA (2, 4 and 8 mg/kg) inhibited the development of tolerance to the analgesic but not to the hypothermic action of U-50,488H. Multiple injections of U-50,488H resulted in a slower gain in body weight which was not modified by treatment with NMMA. The results indicate that inhibition of nitric oxide synthase can selectively block the tolerance to its analgesic action in the rat.