Acute morphine tolerance was induced in mice by subcutaneous (s.c.) injection of a high dose (30 or 100 mg/kg) of morphine. The degree of tolerance was estimated 5 h later. Intracerebroventricular (i.c.v.) injection of graded doses of oxytocin (OXT) dose-dependently attenuated the development of tolerance. i.c.v. injection of a specific anti-OXT serum, on the other hand, facilitated the development of tolerance. Neither OXT nor anti-OXT serum had any effect on the pain sensitivity in morphine-naive mice; nor did these treatments modify the antinociceptive action of a single morphine treatment. It is concluded that the endogenous OXT of the mouse brain is normally involved in the adaptive response of the organism, leading to the development of morphine tolerance.