Morphine administration has been associated with a decrease in hepatic glutathione (GSH) and an increase in the hepatotoxicity of compounds dependent upon GSH for detoxification. In this study, intraperitoneal administration of 100 mg/kg morphine in mice resulted in approximately a 25% decrease in hepatic GSH. The same magnitude of GSH depletion was also observed following intracerebroventricular (i.c.v.) injection of 100 micrograms of morphine, but no effect was observed when 100 micrograms of morphine was administered intravenously. Pretreating animals with either yohimbine (5 mg/kg, i.p.) or prazosin (5 mg/kg, i.p.) resulted in a partial blockade of i.c.v. morphine-induced change in hepatic glutathione concentrations. Adrenalectomy prior to i.c.v. morphine treatment completely prevented morphine-induced changes in hepatic GSH concentrations; however, the morphine response was restored in adrenalectomized mice supplemented with hydrocortisone (2.5 mg/kg). No effect on the ability of i.c.v. morphine to diminish GSH concentrations in the liver was observed following pretreatment with either propranolol (20 mg/kg, i.p.), atropine (1 mg/kg, i.p.), hexamethonium (15 mg/kg, s.c.), or destruction of peripheral adrenergic nerve terminals with 6-hydroxydopamine (30 mg/kg, i.p.). It is concluded that hepatocellular GSH concentrations may be diminished as a consequence of a central action of morphine. The response by liver GSH to this action does not appear to be mediated through adrenal medullary release of catecholamines or by autonomic stimulation of the liver. While corticosteroids are a necessary component of this response, their role is probably permissive. The ability of both prazosin and yohimbine to antagonize the effect of i.c.v. morphine on hepatic GSH, coupled with the apparent absence of a peripheral catecholaminergic mechanism, suggests that the adrenergic interaction with the i.c.v. morphine effect is also of central origin. Thus, the results of this study show that the central effects of morphine can result in a decrease in hepatic GSH, and that this effect is not mediated by a peripheral catecholaminergic mechanism.