Selectively targeting delta opioid receptor subtypes to control drinking behavior

描述（由申请人提供）：同时发生的酒精使用障碍和抑郁/焦虑障碍的治疗强调了NIAAA认可的需要，以确定治疗酒精中毒及其合并症的新靶点/药物。纳曲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，纳曲酮在治疗寻求酗酒者方面显示出高度可变的效果，并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，纳曲酮的非选择性可能导致了不同的疗效和/或限制依从性的副作用。在这里，我们建议具体检查delta阿片受体（DOR）亚型，DOR1和DOR2在酒精相关行为中的作用。我们对DOR作为研究目标特别感兴趣，因为它涉及酒精消耗和焦虑，这通常与酒精滥用共病，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DOR1和DOR2亚型的药物对乙醇消耗具有相反的作用。此外，我们发现DOR2的拮抗剂和DOR1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点。我们也有初步证据表明DOR1可能是DOR和mu阿片受体（MOR）的异源二聚体。在本提案中，我们将研究哪些市售DOR配体对减少乙醇消耗和乙醇戒断诱导的焦虑有效。我们还将研究长时间的乙醇暴露是否会改变DOR配体的效力和/或功效，特别是亚型选择性配体。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MOR，这可能表明它们靶向DOR/MOR异源二聚体来发挥其作用。总之，这些研究可能验证DOR作为酒精滥用障碍的靶点，确定最理想的酒精滥用障碍配体的药理学特征，并可能为MOR/DOR异二聚体作为靶点提供体内相关性。

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.