LACK OF THE DEVELOPMENT OF MORPHINE-TOLERANCE IN EXPERIMENTAL AMNESIA- ROLE OF ARGININE VASOPRESSIN

The development of tolerance to morphine analgesia in amnesic model mi ce and the role of arginine vasopressin (AVP) in the underlying mechan ism was examined. Hypoxia, brain ischemia, scopolamine and electroconv ulsive shock (ECS) manipulation caused amnesia in the step-through typ e passive avoidance learning test performed at 24 h after the training trial. The amnesic state lasted for at least 3 days and recovered to naive control level on the 20th day after each manipulation. In all am nesic groups, radioimmunoassayable AVP content in hypothalamus was dec reased, in particular, the reduction was significant in hypoxia and is chemia induced amnesic animals, then recovered to the control level by 20 days after each treatment. Daily morphine, 10 mg/kg, s.c. easily r esulted in the development of tolerance to the analgesic effect in con trol animals; however, such treatment failed to develop tolerance in a mnesic model animals, leaving the analgesic effect unchanged to the co ntrol levels. Daily pretreatment with i.c.v. AVP, dose-dependently rei nstated the development of tolerance in amnesic model mice. When morph ine injection was started from 20 days after the amnesia inducing trea tment, tolerance developed as in a similar pattern as in control anima ls. Thus, amnesic model mice are deficient in brain AVP levels, and co nsequently, a certain level of AVP in the hypothalamus is required for maintaining the normal function such as the development of tolerance to morphine and the recovery from amnesia.