Selectively targeting delta opioid receptor subtypes to control drinking behavior

说明(由申请人提供)：酒精使用障碍和抑郁/焦虑障碍的治疗强调了NIAAA承认的确定治疗酒精中毒及其共病的新靶点/药物的必要性。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为数不多的疗法之一，证实阿片受体系统是酒精滥用的相关靶点。然而，纳曲酮在治疗寻求酗酒者时表现出高度可变的有效性，并受到副作用的困扰，因此缺乏服药依从性。我们认为，纳曲酮的非选择性性质可能是导致疗效不同和/或副作用限制依从性的原因之一。在这里，我们建议具体研究增量阿片受体(DOR)亚型DOR1和DOR2在酒精相关行为中的作用。我们对DOR作为目标特别感兴趣，因为它与饮酒和焦虑有关，后者往往与酗酒并存，是复发的关键风险因素。在我们的初步研究中，我们发现针对DOR1和DOR2亚型阿片受体的药物对酒精消费具有相反的影响。此外，我们还发现DOR2上的拮抗剂和DOR1上的激动剂可以协同作用减少乙醇消耗，这清楚地表明这两种受体亚型是截然不同的作用靶点。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。在这项建议中，我们将研究哪些商业上可用的DOR配体对于减少酒精消耗和酒精戒断引起的焦虑有效。我们还将研究长期接触乙醇是否会改变DOR配体的效力和/或效力，特别是亚型选择性配体。作为第三个目标，我们将确定是否有任何DOR药物的作用需要其他阿片受体的表达，特别是MOR，这可能表明它们针对DOR/MOR异源二聚体发挥其作用。总之，这些研究可能验证DOR作为酒精滥用障碍的靶点，确定治疗酒精滥用障碍的最理想配体的药理学特征，并可能为MOR/DOR异源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.