Stereospecific effects of a kappa-opiate antagonist on the actions of morphine in morphine-tolerant rats.

The effects of kappa-opiate receptor antagonist, MR 2266 and its dextro isomer, MR 2267 on morphine-induced analgesia and changes in colonic temperature were determined in morphine-naive and morphine-tolerant male Sprague-Dawley rats. Intraperitoneal administration of morphine (8 mg/kg) produced analgesia and hyperthermia in morphine-naive rats. MR 2266 (0.3-3.0 mg/kg) antagonized morphine-induced analgesia and hyperthermia in morphine-naive rates but MR 2267 was inactive. Subcutaneous implantation of six morphine pellets during a 7 day period induced tolerance to the analgesic and hyperthermic effects of morphine in the rat. MR 2266 also antagonized morphine analgesia and hyperthermia in morphine-tolerant rats, however, MR 2267 had no effect. A high dose (3 mg/kg) of MR 2266 produced an intense hypothermic response in morphine-tolerant rats. Previously we have shown that kappa-opiate receptor agonists antagonize morphine analgesia in morphine-naive rats but potentiate it in morphine-tolerant rats. The results of the present studies indicate that the antagonist of kappa-opiate receptors, on the other hand, antagonize morphine effects in both morphine-naive and morphine-tolerant rats in a stereospecific manner.