Laboratory of the Biology of Addictive Diseases, Rockefeller University, New York, NY, USA.
Neuropsychopharmacology. 2018 Mar;43(4):739-750. doi: 10.1038/npp.2017.205. Epub 2017 Aug 31.
The κ-opioid receptor (KOP-r) system and its endogenous ligands, the dynorphins, are involved in the neurobiological regulation of addictive states, and of mood. There are limited data on the impact of selective KOP-r antagonism in humans on basic biobehavioral functions, or on addictive diseases and mood disorders. Previously studied selective KOP-r antagonists have unusual pharmacodynamic and pharmacokinetic properties (slow development of KOP-r selectivity, extremely long duration of action) that limit translation to human studies. A recently developed selective KOP-r-antagonist, Opra Kappa (LY2456302; CERC-501), has medication-like duration of action, oral bioavailability, and target engagement. The current study is the first investigation of the effects of a KOP-r-antagonist in cocaine-dependent persons in comparison with normal volunteers. In a stress-minimized inpatient setting, we determined the neuroendocrine and neurobehavioral effects of repeated administration of an active dose of Opra Kappa (10 mg p.o. daily, four consecutive days in comparison with an initial baseline day). Healthy volunteers (n=40), persons diagnosed with cocaine dependence in early abstinence (<2 months, EACD) (n=23), and drug-free former cocaine-dependent persons (7-month to 25-year abstinence, DFFCD) (n=7) were studied, with measurements including circulating neuroendocrine hormones, affect, and, in cocaine-dependent persons, cocaine craving. Modest adverse events related to Opra Kappa included pruritus, observed in a subset of individuals. No significant change was observed in serum prolactin levels following Opra Kappa administration, but modest increases in circulating adrenocorticotropic hormone and cortisol were observed. No significant changes were noted in measures of depression or cocaine craving in this stress-minimized setting. Overall, these studies demonstrate that effects of 10 mg Opra Kappa are largely consistent with those predicted for a selective KOP-r antagonist. This medication regimen was tolerable, and is therefore feasible for further studies in cocaine-dependent persons.
κ-阿片受体（KOP-r）系统及其内源性配体强啡肽参与成瘾状态和情绪的神经生物学调节。目前关于选择性 KOP-r 拮抗剂在人类基本生物行为功能、成瘾性疾病和情绪障碍中的影响的数据有限。以前研究过的选择性 KOP-r 拮抗剂具有不寻常的药效动力学和药代动力学特性（KOP-r 选择性发展缓慢，作用持续时间极长），限制了其在人类研究中的转化。最近开发的选择性 KOP-r 拮抗剂 Opra Kappa（LY2456302；CERC-501）具有类似药物的作用持续时间、口服生物利用度和靶标结合。本研究是首次在可卡因依赖者中与正常志愿者比较，研究 KOP-r 拮抗剂的作用。在应激最小化的住院环境中，我们确定了重复给予 Opra Kappa（10mg po 每日一次，连续四天，与初始基线日相比）的神经内分泌和神经行为效应。研究了健康志愿者（n=40）、早期戒断（<2 个月，EACD）的可卡因依赖者（n=23）和无毒品的前可卡因依赖者（戒断 7 个月至 25 年，DFFCD）（n=7），测量包括循环神经内分泌激素、情绪，以及可卡因依赖者的可卡因渴求。与 Opra Kappa 相关的轻微不良事件包括瘙痒，在一部分人群中观察到。Opra Kappa 给药后血清催乳素水平无明显变化，但循环促肾上腺皮质激素和皮质醇略有增加。在这种应激最小化环境中，没有注意到抑郁或可卡因渴求的测量值有显著变化。总体而言，这些研究表明，10mg Opra Kappa 的作用与预测的选择性 KOP-r 拮抗剂的作用基本一致。这种给药方案是可耐受的，因此对于可卡因依赖者的进一步研究是可行的。
