Shippenberg T S, LeFevour A, Thompson A C
Integrative Neuroscience Unit, Behavioral Neuroscience Branch, NIDA Division of Intramural Research, Baltimore, MD 21224, USA.
Eur J Pharmacol. 1998 Mar 12;345(1):27-34. doi: 10.1016/s0014-2999(97)01614-2.
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.
使用无偏倚的位置偏爱条件化程序，研究了κ-阿片受体激动剂U69593减弱对吗啡和可卡因条件性奖赏效应产生的敏化和交叉敏化的能力。还评估了U69593处理对可卡因敏化和交叉敏化的影响。在未接触过药物的大鼠中未能产生条件反应的吗啡剂量（1.0 - 5.0 mg·kg⁻¹），在先前每天一次注射吗啡（5.0 mg·kg⁻¹；皮下注射）或可卡因（每天10.0 mg·kg⁻¹；腹腔注射）共5天的动物中，产生了对药物配对位置的明显偏爱。在吗啡治疗方案的第3 - 5天或第1 - 5天接受吗啡与U69593（每天0.04 - 0.32 mg·kg⁻¹；皮下注射）联合给药的动物中，也出现了吗啡诱导的位置偏爱。相比之下，在接受U69593与可卡因联合给药5天的动物中，吗啡未能产生显著的条件化。在未接触过药物的大鼠中未能产生条件反应的可卡因剂量（1.0 - 5.0 mg·kg⁻¹），在接受每天一次注射可卡因（每天10.0 mg·kg⁻¹×5天；腹腔注射）或吗啡（每天5.0 mg·kg⁻¹×5天；皮下注射）的动物中，产生了对药物配对位置的偏爱。在五天可卡因治疗的第3 - 5天或第1 - 5天接受U69593的动物中，未出现可卡因诱导的条件化增强。然而，在接受U69593与吗啡联合给药5天的动物中，对可卡因的反应仍增强。这些发现证实了可卡因和吗啡的条件性奖赏效应会产生敏化和交叉敏化。它们还表明，κ-阿片受体激动剂预防这些敏化反应发展的能力取决于所使用的致敏剂。U69593可预防可卡因诱导的敏化和交叉敏化，但不改变吗啡诱导的敏化或吗啡给药后对可卡因产生的交叉敏化。
