Shoblock James R, Wichmann Jürgen, Maidment Nigel T
Department of Psychiatry and Biobehavioral Sciences, University of California-Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90024, USA.
Neuropharmacology. 2005 Sep;49(4):439-46. doi: 10.1016/j.neuropharm.2005.04.008.
ORL-1 agonists have been proposed as potential therapeutics for substance abuse based on their propensity to counter the effects of mu opioid agonists in several systems, and to inhibit mesolimbic dopamine release, while mostly being devoid of aversive properties. In support of this, ORL-1 agonists have been shown to block the acquisition of morphine conditioned place preference (CPP). We investigated the effect of Ro 64-6198, a systemically active ORL-1 agonist, on the acquisition, expression, extinction, and reinstatement of morphine (20 mg/kg, s.c.) CPP in C57BL6/J mice. Similar to effects obtained with nociceptin/orphanin FQ, Ro 64-6198 (1 mg/kg, i.p.) blocked the acquisition of morphine CPP when given 15 min prior to each drug and vehicle conditioning session. This effect was not due to state dependent learning, since when tested again in the presence of Ro 64-6198 or vehicle no CPP was observed. Administration of Ro 64-6198 (0.3 or 1 mg/kg, i.p.) on the test day alone, in a separate group of animals, failed to block the expression of morphine CPP. Another group of mice was conditioned to morphine to develop CPP, and then exposed to the CPP chambers in the absence of drug once a day for 30 min to extinguish the CPP. Ro 64-6198 (1 mg/kg, i.p.) given 15 min prior to each session during extinction did not affect the rate of extinction. Finally, another group was conditioned to morphine, their CPP extinguished and subsequently reinstated by a priming injection of morphine (20 mg/kg, s.c.). Ro 64-6198 (1 mg/kg, i.p.), given 15 min prior to the priming injection, blocked reinstatement of morphine CPP. These results suggest that Ro 64-6198's effects may be limited to attenuation of the acute rewarding effects of morphine.
基于在多个系统中对抗μ阿片受体激动剂作用以及抑制中脑边缘多巴胺释放的倾向，且大多没有厌恶特性，孤儿受体-1（ORL-1）激动剂已被提议作为治疗药物滥用的潜在疗法。为此，研究表明ORL-1激动剂可阻断吗啡条件性位置偏爱（CPP）的形成。我们研究了具有全身活性的ORL-1激动剂Ro 64-6198对C57BL6/J小鼠吗啡（20 mg/kg，皮下注射）CPP的形成、表达、消退和恢复的影响。与痛敏肽/孤啡肽FQ的作用相似，Ro 64-6198（1 mg/kg，腹腔注射）在每次药物和溶剂条件训练前15分钟给药时，可阻断吗啡CPP的形成。此效应并非由于状态依赖性学习，因为在Ro 64-6198或溶剂存在的情况下再次测试时，未观察到CPP。单独在测试日对另一组动物给予Ro 64-6198（0.3或1 mg/kg，腹腔注射），未能阻断吗啡CPP的表达。另一组小鼠用吗啡进行条件训练以形成CPP，然后每天一次在无药物的情况下暴露于CPP实验箱30分钟以消退CPP。在消退期间每次训练前15分钟给予Ro 64-6198（1 mg/kg，腹腔注射）并不影响消退速率。最后，另一组小鼠用吗啡进行条件训练，其CPP消退，随后通过一次吗啡（20 mg/kg，皮下注射）激发注射使其恢复。在激发注射前15分钟给予Ro 64-6198（1 mg/kg，腹腔注射）可阻断吗啡CPP的恢复。这些结果表明，Ro 64-6198的作用可能仅限于减弱吗啡的急性奖赏效应。
