Cross-tolerance between analgesic low doses of morphine and naloxone in arthritic rats

The effects of acute injections of naloxone (3-3000 micrograms/kg i.v.) and morphine (100-1000 micrograms/kg i.v.) on the vocalization threshold induced by pressure on the paw were analyzed in adjuvant-induced arthritic rats pretreated either with naloxone or with morphine administered at low doses (9 micrograms/kg s.c. and 3000 micrograms/kg s.c., respectively) over 4 consecutive days. In naloxone-pretreated arthritic rats, the paradoxical analgesic effect of low doses of naloxone was almost abolished, and the potent analgesic effects of low doses of morphine were also strongly and dose-dependently reduced. In morphine-pretreated arthritic animals, the analgesic effect of low doses of naloxone was significantly attenuated. These results attest that a cross-tolerance with low analgesic doses of morphine and naloxone can be demonstrated in these chronic suffering animals. By contrast, in rats pretreated either with naloxone or morphine, the hyperalgesic effect of naloxone produced by higher doses persisted and even was unmasked for doses which were analgesic before the pretreatment. These data emphasize the involvement of opiate receptors different in their sensitivity and/or their functions in the two opposite effects of naloxone. They also suggest that opiate receptors and endorphinergic systems differ in normal animals and animals which experience persistent pain.