The Rise and Fall of Kappa-Opioid Receptors in Drug Abuse Research.
The Rise and Fall of Kappa-Opioid Receptors in Drug Abuse Research.
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DOI：
10.1007/164_2019_268
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发表时间：
2020
影响因子：
--
通讯作者：
Banks ML
中科院分区：
文献类型：
--
作者：
Banks ML
药物使用障碍是一个全球公共卫生问题。据推测，这种精神健康障碍是由于长期药物暴露导致的神经生物学变化引起的，临床上表现为对滥用物质的采购和使用的不适当的行为分配，以及远离由更具适应性的非药物强化物维持的其他行为（例如社会关系、工作）。强啡肽/κ-阿片受体 (KOR) 是一种受体系统，实验动物和人类长期接触滥用药物（例如可卡因、阿片类药物、酒精）后会发生改变；涉及强啡肽/KOR 系统在物质使用障碍的表达、机制和治疗中的作用。在某些实验条件下，KOR 拮抗剂可以减少实验动物的药物自我给药，但在其他条件下则不然。最近，一些人体实验室和临床试验评估了 KOR 拮抗剂作为可卡因或烟草使用障碍候选药物疗法的有效性，以检验临床前研究产生的假设。 KOR 拮抗剂未能显着改变人类的药物使用指标，这表明一些临床前药物自我给药研究之间的翻译不一致，与其他提供同时获得替代非药物强化剂（例如食物）的临床前药物自我给药研究一致。讨论了这种翻译不一致的含义以及检查 KOR 激动剂或拮抗剂作为候选物质使用障碍药物疗法的治疗潜力的未来方向。
Substance use disorders represent a global public health issue. This mental health disorder is hypothesized to result from neurobiological changes as a result of chronic drug exposure and clinically manifests as inappropriate behavioral allocation towards the procurement and use of the abused substance and away from other behaviors maintained by more adaptive nondrug reinforcers (e.g. social relationships, work). The dynorphin/kappa-opioid receptor (KOR) is one receptor system that has been altered following chronic exposure to drugs of abuse (e.g. cocaine, opioids, alcohol) in both laboratory animals and humans; implicating the dynorphin/KOR system in the expression, mechanisms, and treatment of substance use disorders. KOR antagonists have reduced drug self-administration in laboratory animals under certain experimental conditions, but not others. Recently, several human laboratory and clinical trials have evaluated the effectiveness of KOR antagonists as candidate pharmacotherapies for cocaine or tobacco use disorder to test hypotheses generated from preclinical studies. KOR antagonists failed to significantly alter drug use metrics in humans suggesting translational discordance between some preclinical drug self-administration studies and consistent with other preclinical drug self-administration studies that provide concurrent access to an alternative nondrug reinforcer (e.g. food). The implications of this translational discordance and future directions for examining the therapeutic potential of KOR agonists or antagonists as candidate substance use disorder pharmacotherapies are discussed.