Occupancy of the kappa opioid receptor by naltrexone predicts reduction in drinking and craving
Occupancy of the kappa opioid receptor by naltrexone predicts reduction in drinking and craving
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DOI：
10.1038/s41380-020-0811-8
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发表时间：
2020-06-15
影响因子：
11
通讯作者：
Krishnan-Sarin, Suchitra
中科院分区：
文献类型：
--
作者：
de Laat, Bart;Nabulsi, Nabeel;Krishnan-Sarin, Suchitra
纳曲酮治疗酒精使用障碍(AUD)的疗效不大。更好地了解纳曲酮效应背后的神经生物学可能会优化治疗。我们用[C-11]-LY2795050正电子发射断层扫描(PET)评估纳曲酮对kappa阿片受体(KOR)的占有率，作为预测纳曲酮疗效的指标。对纳曲酮的反应定义为每天服用100 mg纳曲酮1周前后渴望程度的差异和饮酒范例(ADP)中饮酒次数的差异。纳入了44名(14华氏度)未接受治疗的重度饮酒者，这些人符合澳门氏症的标准。参与者每周饮酒47+/-16杯，在家族酗酒史(FH，26例阳性)中处于平衡状态。实现了高KOR入住率(92+/-1%)。在FH阳性而不是FH阴性的参与者中，居住率与饮酒年限呈负相关(t(3，42)=4.00，p=0.0003)。纳曲酮对KOR的占有率越高，在ADP期间酒精渴求越高(F-1，F-81=4.88，p=0.030)。纳曲酮治疗后饮酒量的减少与KOR的占有率呈负相关，对FH状态有显著影响(t(1，43)=-2.08，p=0.044)。包括KOR占有率、YOD和FH变量在内的Logistic回归模型对饮酒量的预测准确率为84%。这些结果证实了纳曲酮结合在KOR部位，并提示纳曲酮对KOR的占位可能与临床反应有关。基于我们的结果，我们认为MU和KOR的不同亲和力可以解释为什么较低剂量的纳曲酮可以有更好的临床疗效。
The efficacy of naltrexone to treat alcohol use disorder (AUD) is modest. A better understanding of the neurobiology underlying naltrexone effects could optimize treatments. We evaluated the occupancy of the kappa opioid receptor (KOR) by naltrexone measured with [C-11]-LY2795050 positron emission tomography (PET) as a predictor of response to naltrexone. Response to naltrexone was defined as the difference in craving and the difference between the number of drinks consumed during an alcohol drinking paradigm (ADP) before and after 1 week of supervised 100 mg daily oral naltrexone. Forty-four (14 F) nontreatment seeking heavy drinkers meeting criteria for AUD were enrolled. Participants drank 47 +/- 16 drinks per week and were balanced in family history of alcoholism (FH, 26 positive). High KOR occupancy (92 +/- 1%) was achieved. Occupancy was negatively associated with number of years drinking (YOD) in FH positive, but not FH negative, participants (t(3,42) = 4.00,p = 0.0003). Higher KOR occupancy by naltrexone was associated with higher alcohol craving during the ADP (F-1,F-81 = 4.88,p = 0.030). The reduction in drinking after naltrexone was negatively associated with KOR occupancy, with significant effects of FH status (t(1,43) = -2.08,p = 0.044). A logistic regression model including KOR occupancy, YOD, and FH variables achieved an 84% prediction accuracy for >= 50% reduction in drinking. These results confirm that naltrexone binds at the KOR site and suggest that KOR occupancy by naltrexone may be related to clinical response. Based on our results, we propose that differential affinities for the mu and KOR could explain why lower doses of naltrexone can have greater clinical efficacy.