Opiates and thermoregulation in mice. IV. Tolerance and cross-tolerance

We have previously shown in mice that opiate agonists produce either hypothermia or hyperthermia or both, depending on the dose used and the ambient temperature. We have also shown that both temperature effects are blocked by the antagonists, naloxone and naltrexone. In order to confirm that these are specific opiate effects, the present studies to explore the development of tolerance to both temperature effects were undertaken. Mice were treated chronically with twice-daily injections of 2.5, 10, 40 or 160 mg/kg of morphine sulfate. Rectal temperature changes were monitored at 20 degrees, 25 degrees or 30 degrees C ambient temperature after the initial injection and at weekly intervals thereafter. At 20 degrees and 25 degrees C, the initial hypothermic response was replaced by hyperthermia after 7 weeks of twice-daily injections. At 30 degrees C, the initial hyperthermia became more pronounced and no evidence of tolerance was seen at any dose. A challenge dose of 160 mg/kg was given to all animals at 20 degrees C ambient temperature after 9 weeks of injections. There was a diminution of the hypothermic response inversely related to the chronically administered dose. At 30 degrees C, the 160 mg/kg challenge dose at 9 weeks showed little evidence of tolerance to the hyperthermia. Morphine-base pellet implantation, however, resulted in profound tolerance to both the hypo- and hyperthermic response within 1 day after implantation, peaking at 4 days and somewhat reduced by 1 week. Tolerance to the hypothermic effects induced by chronic administration of levorphanol and morphine-levorphanol cross-tolerance was also observed. It appears that both the hypo- and hyperthermia induced by the opiate and opioid agonists are opiate receptor effects because both effects can be blocked by the opiate antagonists and tolerance and cross-tolerance can be developed to both effects as well.