Dose-effect curves were obtained for the influence of naltrexone, of naloxone and of morphine on lever-pressing responses of squirrel monkeys and key-pecking responses of pigeons maintained by food presentation during fixed-interval (FI) and fixed-ratio (FR) components of a multiple schedule. Morphine caused dose-related decreases in FI and FR responding, with complete suppression occurring after 3 mg/kg was administered to monkeys and after 10 mg/kg was administered to pigeons. Naltrexone doses as low as 0.03 mg/kg (monkeys) or 0.1 mg/kg (pigeons) and naloxone doses as low as 0.1 mg/kg (monkeys) or 1 mg/kg (pigeons) shifted morphine dose-effect curves by one or more log units to the right. The effects of a 3 mg/kg injection of morphine were blocked completely by naltrexone (0.1-0.3 mg/kg) injected up to 16 hr before morphine, but not by naloxone (0.3-1 mg/kg) injected more than 2 hr before morphine. Thus, naltrexone was 3 to 10 times more potent than naloxone as an antagonist of morphine and was longer acting. Given alone, only high doses of naltrexone or naloxone (10 mg/kg, monkeys; 56 mg/kg, pigeons) had pronounced actions; FR and FI responding were markedly decreased and vomiting often occurred. Repeated daily injections of these high doses of naltrexone or naloxone resulted in little or no tolerance. One to 6 months after termination of chronic treatment, dose-effect curves for naltrexone on FR and FI responding maintained by food presentation were shifted markedly to the left with the monkeys, but not with the pigeons.