Sukhtankar Devki D, Lagorio Carla H, Ko Mei-Chuan
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Department of Psychology, University of Wisconsin-Eau Claire, Eau Claire, WI 54702, USA.
Eur J Pharmacol. 2014 Dec 15;745:182-9. doi: 10.1016/j.ejphar.2014.10.029. Epub 2014 Oct 29.
Nociceptin/orphanin FQ peptide (NOP) receptor agonists attenuate morphine-induced conditioned place preference in rodents. However, it is not known whether NOP agonists have reinforcing properties or can inhibit mu opioid receptor (MOP)-mediated reinforcement as measured by drug self-administration in rodents. Further understanding the behavioral effects of NOP agonists could suggest them as having potential in attenuating reinforcing effects of opioids. In the first part of the study, reinforcing properties of selective NOP agonist SCH221510 were determined and compared with the full MOP agonist remifentanil under fixed-ratio 5 (FR5) and progressive-ratio (PR) schedules of drug self-administration. In the second part, effects of systemic and intracisternal pretreatment of SCH221510 were determined and compared with MOP antagonist naltrexone in attenuating reinforcing effects of remifentanil and a non-drug reinforcer (sucrose pellets). Remifentanil self-administration (0.3-10 µg/kg/infusion) generated a biphasic dose-response curve, characteristic of drugs with reinforcing properties. SCH221510 (3-300 µg/kg/infusion) self-administration resulted in flat dose-response curves and early break-points under the PR, indicative of drugs lacking reinforcing value. Intracisternally, but not systemically, administered SCH221510 (0.3-3 µg) attenuated remifentanil self-administration, comparable with systemic naltrexone (0.03-0.3 mg/kg). SCH221510 (1-3 µg), unlike naltrexone (0.03-1 mg/kg), attenuated responding for sucrose pellets. Both effects of SCH221510 were reversed by the NOP antagonist J-113397 (0.3-3 µg). These results suggest that SCH221510 does not function as a reinforcer in rats, and that it can attenuate the reinforcing value of MOP agonists; therefore, the potential utility of NOP agonists for the treatment of drug addiction warrants further evaluation.
孤啡肽/痛敏肽（NOP）受体激动剂可减弱啮齿动物中吗啡诱导的条件性位置偏爱。然而，尚不清楚NOP激动剂是否具有强化特性，或者是否能像通过啮齿动物药物自我给药所测量的那样抑制μ阿片受体（MOP）介导的强化作用。进一步了解NOP激动剂的行为效应可能表明它们在减弱阿片类药物强化作用方面具有潜力。在研究的第一部分，在固定比率5（FR5）和渐进比率（PR）药物自我给药方案下，确定了选择性NOP激动剂SCH221510的强化特性，并与完全MOP激动剂瑞芬太尼进行了比较。在第二部分中，确定了SCH221510全身和脑池内预处理的效果，并与MOP拮抗剂纳曲酮在减弱瑞芬太尼和非药物强化物（蔗糖颗粒）强化作用方面进行了比较。瑞芬太尼自我给药（0.3 - 10μg/kg/输注）产生了双相剂量反应曲线，这是具有强化特性药物的特征。SCH221510（3 - 300μg/kg/输注）自我给药导致PR下的剂量反应曲线平坦且早期断点出现，表明药物缺乏强化价值。脑池内而非全身给予的SCH221510（0.3 - 3μg）减弱了瑞芬太尼自我给药，与全身给予的纳曲酮（0.03 - 0.3mg/kg）相当。与纳曲酮（0.03 - 1mg/kg）不同，SCH221510（1 - 3μg）减弱了对蔗糖颗粒的反应。SCH221510的这两种作用均被NOP拮抗剂J - 113397（0.3 - 3μg）逆转。这些结果表明，SCH221510在大鼠中不具有强化剂的功能，并且它可以减弱MOP激动剂的强化价值；因此，NOP激动剂在治疗药物成瘾方面的潜在效用值得进一步评估。
