Antagonism to morphine analgesia and involvement in morphine tolerance of angiotensin II in periaqueductal gray of the rabbits

The stainless steel cannulas were implanted to male rabbits of 2.0-2.6 kg, under Na-pentobarbital anaesthesia with the aid of a stereotaxic instrument. Co-ordinates of the locations of the implantations were P 9.5, LR 1.0, H 10.0 mm (under outer surface of the skull) on both sides of periaqueductal gray (PAG). After 1 wk, nociception was assessed by measuring the latency of the escape response (ERL) elicited by strong radiant heat focused on the nose of rabbits. The analgesic effect of morphine (4 mg/kg, iv) was blocked by injecting angiotensin II (AII, 0.1 microgram) into PAG (P less than 0.01, ANOVA), but not by injecting the same dose of AII into the vicinity of PAG (P greater than 0.05, ANOVA). Morphine tolerance was induced by iv infusion of morphine for 2 d, the dose being 50 mg/(kg.8 h) on d 1 and 75 mg/(kg.8 h) on d 2. On d 3, the degree of tolerance was checked by the analgesia induced by iv morphine 4 mg/kg. Tolerance was partly reversed by injecting AII anti-serum 2 microliters into PAG(P less than 0.01, ANOVA). The results suggest that AII in PAG is antagonistic to morphine analgesia and is involved in the development of morphine tolerance.