Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, New York.
Alcohol Clin Exp Res. 2019 Jun;43(6):1077-1090. doi: 10.1111/acer.14033. Epub 2019 May 2.
Nalfurafine is the first clinically approved kappa-opioid receptor (KOP-r) agonist as an antipruritus drug with few side effects in humans (e.g., sedation, depression, and dysphoria). No study, however, has been done using nalfurafine on alcohol drinking in rodents or humans.
We investigated whether nalfurafine alone or in combination with mu-opioid receptor (MOP-r) antagonist naltrexone changed excessive alcohol drinking in male and female C57BL/6J (B6) mice subjected to a chronic intermittent-access drinking paradigm (2-bottle choice, 24-hour access every other day) for 3 weeks. Neuronal proopiomelanocortin enhancer (nPE) knockout mice with brain-specific deficiency of beta-endorphin (endogenous ligand of MOP-r) were used as a genetic control for the naltrexone effects.
Single administration of nalfurafine decreased alcohol intake and preference in both male and female B6 mice in a dose-dependent manner. Pretreatment with nor-BNI (a selective KOP-r antagonist) blocked the nalfurafine effect on alcohol drinking, indicating a KOP-r-mediated mechanism. Pharmacological effects of a 5-dosing nalfurafine regimen were further evaluated: The repeated nalfurafine administrations decreased alcohol consumption without showing any blunted effects, suggesting nalfurafine did not develop a tolerance after the multidosing regimen tested. Nalfurafine did not produce any sedation (spontaneous locomotor activity), anhedonia-like (sucrose preference test), anxiety-like (elevated plus maze test), or dysphoria-like (conditioned place aversion test) behaviors, suggesting that nalfurafine had few side effects. Investigating synergistic effects between low-dose naltrexone and nalfurafine, we found that single combinations of nalfurafine and naltrexone, at doses lower than individual effective dose, profoundly decreased excessive alcohol intake in both sexes. The effect of nalfurafine on decreasing alcohol consumption was confirmed in nPE-/- mice, suggesting independent mechanisms by which nalfurafine and naltrexone reduced alcohol drinking.
The clinically utilized KOP-r agonist nalfurafine in combination with low-dose naltrexone has potential in alcoholism treatment.
纳呋拉啡是第一种经临床批准的κ阿片受体（KOP-r）激动剂，作为一种抗瘙痒药物，在人类中副作用较少（例如镇静、抑郁和烦躁不安）。然而，尚无研究在啮齿动物或人类中使用纳呋拉啡治疗酒精摄入。
我们研究了纳呋拉啡单独或与μ阿片受体（MOP-r）拮抗剂纳曲酮联合使用是否会改变雄性和雌性 C57BL/6J（B6）小鼠在慢性间歇性接触饮酒范式（2 瓶选择，每隔一天 24 小时接触）下连续 3 周的过度饮酒。使用大脑特异性缺乏β-内啡肽（MOP-r 的内源性配体）的神经元原啡肽增强子（nPE）敲除小鼠作为纳曲酮作用的遗传对照。
单次给予纳呋拉啡可剂量依赖性地减少雄性和雌性 B6 小鼠的酒精摄入量和偏好。纳呋拉啡对酒精摄入的作用被 nor-BNI（一种选择性 KOP-r 拮抗剂）阻断，表明这是一种 KOP-r 介导的机制。进一步评估了 5 次纳呋拉啡给药方案的药理作用：重复给予纳呋拉啡可减少酒精消耗，而没有表现出任何作用减弱的迹象，这表明在测试的多剂量方案后，纳呋拉啡没有产生耐受性。纳呋拉啡不会产生镇静（自发运动活动）、快感缺失样（蔗糖偏好测试）、焦虑样（高架十字迷宫测试）或烦躁样（条件性位置厌恶测试）行为，表明纳呋拉啡的副作用较少。研究低剂量纳曲酮与纳呋拉啡联合应用的协同作用时，我们发现，纳呋拉啡和纳曲酮的单一组合，剂量低于单独有效剂量，可显著减少两性的过度饮酒。在 nPE-/- 小鼠中证实了纳呋拉啡降低酒精摄入量的作用，这表明纳呋拉啡和纳曲酮降低酒精摄入的作用机制不同。
临床上使用的 KOP-r 激动剂纳呋拉啡与低剂量纳曲酮联合使用具有治疗酗酒的潜力。
