To characterize further the hypoglycemic effect of intrathecally (i.t.) administered morphine, species and drug specificity, effects of morphine-induced tolerance and pentobarbital-induced anesthesia and effects on liver glycogen were studied in nonfasted animals. In rats, morphine (125 micrograms i.t.) produced the same behavioral toxicity (scratching, biting, seizures) and hypoglycemia as previously reported in mice. In mice, the glycine antagonist strychnine (5 micrograms i.t.) and the morphine metabolite morphine-3-glucuronide (2 micrograms i.t.) mimicked the behavioral, but not the hypoglycemic, effects of high-dose i.t. morphine. Kainic acid (0.1 micrograms i.t.), which caused high-frequency hindlimb movements, also did not cause hypoglycemia. Naltrexone (1 mg/kg/ s.c.) or the s.c. implantation of morphine pellets for 3 days attenuated the hypoglycemic effect, but not the behavioral effects, of morphine (40 micrograms i.t.). The hyperglycemic effect of s.c. morphine(20 mg/kg) was blocked by i.t. morphine. Anesthesia with pentobarbital (75 mg/kg i.p.) attenuated the hypoglycemic effect of morphine (40 micrograms i.t.). Morphine i.t. also caused a time- and dose-dependent decrease in liver glycogen levels and was more potent in causing glycogenolysis (30 min ED50 = 19 micrograms) than in causing hypoglycemia (30 min ED50 = 30 micrograms). It is concluded that the hypoglycemic effect of i.t. morphine appears to be independent of its behavioral effects, displays tolerance and is accompanied by hepatic glycogen depletion.