Time course and magnitude of tolerance to the analgesic effects of systemic morphine in amphibians.

The systemic administration of morphine (100 nmol/g, s.c.) produced a significant and long-lasting analgesia (up to 8 h) in the Northern grass frog, Rana pipiens. Daily bolus injections of the same dose of morphine or saline for one week resulted in a significant analgesia for 3 days in the morphine group, which fell to levels indistinguishable from the saline-treated controls on days 4 through 7. In separate experiments, animals were treated identically with morphine or saline but were not tested daily for pain thresholds. In these animals, administration of a range of morphine doses on day 8 yielded dose-response curves significantly-shifted rightward by a factor of 3.3 in the morphine-treated group compared to the saline-injected controls. These studies are the first to show the time course of tolerance development and the magnitude of morphine tolerance in a non-mammalian vertebrate species.