Selectively targeting delta opioid receptor subtypes to control drinking behavior

选择性靶向 δ 阿片受体亚型来控制饮酒行为

• 批准号: 8678663
• 负责人: JENNIFER L WHISTLER
• 金额: $ 32.85万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8678663
• 关键词: Adverse effects; Affect; Agonist; Alcohol abuse; Alcohol consumption; Alcohol withdrawal syndrome; Alcohol-Related Disorders; Animals; Anxiety; Anxiety Disorders; Behavioral; Biological; Comorbidity; Consumption; Data; Disease; Drug Receptors; Drug Targeting; Drug usage; Goals; Health Services Research; Intervention; Knock-out; Ligands; Mediating; Mental Depression; Molecular; NIH Program Announcements; Naltrexone; National Institute on Alcohol Abuse and Alcoholism; Nature; Opioid; Opioid Receptor; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Plague; Receptor Gene; Recovery; Relapse; Research Design; Risk Factors; Role; System; Therapeutic; Tissues; Withdrawal; alcohol behavior; alcohol exposure; alcohol response; alcohol use disorder; alcoholism therapy; base; clinical efficacy; delta opioid receptor; design; drinking behavior; in vivo; interest; monomer; mu opioid receptors; novel; problem drinker; receptor; response

DESCRIPTION (provided by applicant): Treatment of Co-Occurring Alcohol Use Disorders and Depression/Anxiety Disorders highlight the need, recognized by the NIAAA, to identify new targets/drugs for the treatment of alcoholism and its co- morbidities. Naltrexone a non-selective opioid receptor antagonist is one of the few therapeutics currently used in the treatment of alcoholism, validating the opioid receptor system as a relevant target for alcohol abuse. However, naltrexone shows highly variable eficacy in treatment seeking alcoholics and is plagued by side effects and consequent lack of compliance of use. We propose that the non-selective nature of naltrexone may be contributing to the variable efficacy and/or the side effects that limit compliance. Here, we propose to examine specifically the role of the delta opioid receptor (DOR) subtypes, DOR1 and DOR2 in alcohol related behaviors. We are particularly intrigued by the DOR as a target because it is involved in both alcohol consumption and anxiety, which is often co-morbid with alcohol abuse and is a key risk factor for relapse. In our preliminary studies we have found that drugs that target the DOR1 and DOR2 subtypes of opioid receptor have opposing effects on ethanol consumption. In addition, we have found that an antagonist at DOR2 and an agonist at DOR1 can act synergistically to reduce ethanol consumption clearly indicating that these two receptor subtypes are distinct targets with opposing actions. We also have preliminary evidence that the DOR1 may be a heterodimer of the DOR and the mu opioid receptor (MOR). In this proposal, we will examine which commercially available DOR ligands are effective for the reduction of ethanol consumption and ethanol withdrawal induced anxiety. We will also examine whether prolonged ethanol exposure alters the potency and/or efficacy of the DOR ligands, in particular the subtype selective ligands. As a third goal, we will determine whether the effects of any of the DOR drugs require expression of the other opioid receptors, in particular the MOR which could indicate that they target a DOR/MOR heterodimer to exert their effects. Together, these studies may validate the DOR as a target for alcohol abuse disorders, indentify the pharmacological profile of the most ideal ligands for alcohol abuse disorders, and perhaps provide in vivo relevance for the MOR/DOR heterodimer as a target.

描述（由申请人提供）：治疗合并酒精使用障碍和抑郁/焦虑障碍强调了NIAAA认识到的识别治疗酒精中毒及其合并症的新靶点/药物的必要性。纳洛酮是一种非选择性阿片受体拮抗剂，是目前用于治疗酒精中毒的少数治疗药物之一，验证了阿片受体系统作为酒精滥用的相关靶点。然而，纳洛酮在寻求治疗的酗酒者中显示出高度可变的有效性，并且受到副作用和随之而来的缺乏使用依从性的困扰。我们认为，纳洛酮的非选择性可能导致可变的疗效和/或限制依从性的副作用。在这里，我们建议专门研究δ阿片受体（DOR）亚型，DOR 1和DOR 2在酒精相关行为中的作用。我们对DOR作为目标特别感兴趣，因为它涉及酒精消费和焦虑，这通常与酒精滥用共存，是复发的关键风险因素。在我们的初步研究中，我们发现靶向阿片受体的DOR 1和DOR 2亚型的药物对乙醇消耗有相反的影响。此外，我们发现DOR 2的拮抗剂和DOR 1的激动剂可以协同作用以减少乙醇消耗，这清楚地表明这两种受体亚型是具有相反作用的不同靶标。我们也有初步证据表明DOR 1可能是DOR和μ阿片受体（莫尔）的异源二聚体。在这个提议中，我们将研究哪些市售DOR配体对于减少乙醇消耗和乙醇戒断诱导的焦虑是有效的。我们还将检查是否延长乙醇暴露改变DOR配体，特别是亚型选择性配体的效力和/或功效。作为第三个目标，我们将确定任何DOR药物的作用是否需要其他阿片受体的表达，特别是莫尔，这可能表明它们靶向DOR/莫尔异二聚体以发挥其作用。总之，这些研究可以验证DOR作为酒精滥用障碍的靶标，鉴定酒精滥用障碍的最理想配体的药理学特征，并且可能提供莫尔/DOR异二聚体作为靶标的体内相关性。