Clinically utilized kappa-opioid receptor agonist nalfurafine combined with low-dose naltrexone prevents alcohol relapse-like drinking in male and female mice.
Clinically utilized kappa-opioid receptor agonist nalfurafine combined with low-dose naltrexone prevents alcohol relapse-like drinking in male and female mice.
复制标题
临床上使用的κ阿片受体激动剂纳芙拉芬与低剂量纳曲酮联合使用可预防雄性和雌性小鼠的酒精复发样饮酒。
DOI：
10.1016/j.brainres.2019.146410
复制
发表时间：
2019
期刊：
影响因子：
2.9
通讯作者：
Kreek,MaryJeanne
中科院分区：
文献类型：
--
作者：
Zhou,Yan;Kreek,MaryJeanne
酒精复发是酒精依赖的治疗目标，也是药物开发的目标。临床上使用的纳呋拉芬（NFF）是一种有效的和选择性的κ-阿片受体（KOP-r）激动剂，具有较少的副作用（例如，镇静或快感缺乏）。我们最近发现NFF通过KOP-r介导的机制减少小鼠过量饮酒。在这里，我们进一步研究了NFF单独（1 - 10 μ g/kg）或与纳洛酮（NTX，μ阿片受体[MOP-r]拮抗剂）组合是否使用小鼠酒精剥夺效应（ADE）范式来模拟人类酗酒者的复发事件，从而改变酒精复发样饮酒。纳美芬（NMF，具有MOP-r拮抗作用的临床使用的KOP-r部分激动剂）用作新的NFF + NTX组合对小鼠ADE的影响的参考化合物。在暴露于3周间歇性饮酒（两瓶选择，每隔一天24小时饮酒）后，雄性和雌性小鼠均显示出过量的酒精摄入，然后在1周戒酒后出现明显的ADE。NFF以剂量依赖性方式预防雄性和雌性小鼠的ADE。NFF与NTX的组合在低于那些个体有效剂量的剂量下降低ADE而没有性别差异，表明两种化合物之间的协同效应。NMF可预防两种性别的ADE，而选择性KOP-r拮抗剂nor-BNI则无此作用。我们的新研究表明，临床使用的强效KOP-r激动剂NFF与低剂量NTX的组合在酒精"复发"治疗中具有治疗潜力。
Alcohol relapse is a treatment goal for alcohol dependence and the target for medications’ development. Clinically utilized nalfurafine (NFF) is a potent and selective kappa- opioid receptor (KOP-r) agonist, with fewer side effects (e.g., sedation or anhedonia) than classic KOP-r full agonists. We have recently found that NFF reduces excessive alcohol drinking in mice via a KOP-r-mediated mechanism. Here, we further investigated whether NFF alone (1–10 μg/kg) or in combination with naltrexone (NTX, mu-opioid receptor [MOP-r] antagonist) altered alcohol relapse-like drinking using a mouse alcohol deprivation effect (ADE) paradigm to mimic the relapse episodes in human alcoholics. Nalmefene (NMF, clinically utilized KOP-r partial agonist with MOP-r antagonism) was used as a reference compound for the effects on mouse ADE of new NFF + NTX combination. After exposed to 3-week intermittent- access alcohol drinking (two-bottle choice, 24-h access every other day), both male and female mice displayed excessive alcohol intake and then pronounced ADE after 1-week abstinence. NFF prevented the ADE in a dose-dependent manner in both male and female mice. A combination of NFF with NTX reduced the ADE without sex differences at doses lower than those individual effective ones, suggesting synergistic effects between the two compounds. NMF prevented the ADE in both sexes, while selective KOP-r antagonist nor-BNI had no effect. Our new study suggests that a combination of clinically-utilized, potent KOP-r agonist NFF with low-dose NTX has therapeutic potential in alcohol “relapse” treatment.