Sensitization to the conditioned rewarding effects of morphine and cocaine: differential effects of the kappa-opioid receptor agonist U69593.

The ability of the kappa-opioid receptor agonist U69593 to attenuate the sensitization and cross-sensitization which develops to the conditioned rewarding effects of morphine and cocaine was examined using an unbiased place-preference conditioning procedure. The influence of U69593 treatment upon sensitization and cross-sensitization to cocaine was also assessed. Doses of morphine (1.0-5.0 mg kg(-1)) which failed to produce a conditioned response in drug-naive rats produced marked preferences for the drug-paired place in animals which had previously received once daily injections of morphine (5.0 mg kg(-1); s.c.) or cocaine (10.0 mg kg(-1); i.p.) for 5 days. Morphine-induced place preferences also occurred in animals which had received morphine in combination with U69593 (0.04-0.32 mg kg(-1); s.c.) on either days 3-5 or 1-5 of the morphine treatment regimen. In contrast, morphine failed to produce significant conditioning in animals which had received U69593 with cocaine for 5 days. Doses of cocaine (1.0-5.0 mg kg(-1)) which did not produce a conditioned response in naive rats produced preferences for the drug-paired place in animals which had received once daily injections of cocaine (10.0 mg kg(-1) day(-1) x 5 days; i.p.) or morphine (5.0 mg kg(-1) day(-1) x 5 days; s.c.). No enhancement of cocaine-induced conditioning occurred in animals which had received U69593 on days 3-5 or on days 1-5 of the five-day cocaine treatment. In animals, however, which had received U69593 with morphine for 5 days, an enhanced response to cocaine was still seen. These findings confirm that sensitization and cross-sensitization develop to the conditioned rewarding effects of cocaine and morphine. They also indicate that the ability of a kappa-opioid receptor agonist to prevent the development of these sensitized responses depends on the sensitizing agent employed. U69593 prevents sensitization and cross-sensitization induced by cocaine, but does not modify morphine-induced sensitization or the cross-sensitization which develops to cocaine after morphine administration.