Single-dose tolerance to morphine hypothermia in the rat: differentiation of acute from long-term tolerance

The time course for the development and disappearance fo tolerance to the hypothermic effects of morphine was determined after a single subcutaneous injection (10 mg/kg) in rats. Body temperature responses to second injections, given at varying times after the first, were compared with those produced by the initial injections. Tolerance (attenuation of the hypothermic response) induced by a single dose of morphine was found to be biphasic. Acute tolerance was apparent by 4.5 hours and lasted at least 20 hours after morphine administration. Development of long-term tolerance occurred within 24 hours, was maximal at 3 days and persisted up to 11 days. Both acute and long-term tolerance were drug specific since hypothermic responses to pentobarbital were not altered either 4.5 or 72 hours after morphine. Long-term tolerance was attenuated by co-administration of naloxone with initial dose of morphine. Long-term tolerance induced by multiple doses of morphine (300 mg/kg/day) differed from that induced by a single dose in persistence (3-4 weeks) rather than in quality or magnitude. The thermoregulatory response of the rat provides a sensitive measurement system which allows discrimination between acute and long-term opiate effects.