Ernest Gallo Clinic and Research Center, Department of Neurology, University of California, San Francisco, Emeryville, California 94608, USA.
Biol Psychiatry. 2009 Oct 15;66(8):777-84. doi: 10.1016/j.biopsych.2009.05.019. Epub 2009 Jul 3.
Opioid receptors are clinically important targets for both pain and alcohol abuse. Three opioid receptors have been cloned: mu, delta, and kappa, all of which effect alcohol consumption in animal models. Naltrexone is a nonselective opioid antagonist used for alcoholism, the clinical utility of which is limited by poor efficacy and adverse side effects. Here, we demonstrate that the therapeutic limitations of naltrexone may reflect its poor selectivity. Despite decades of research, several mysteries surround the pharmacology of these receptors. For example, two pharmacologically defined subtypes of delta receptors exist in vivo.
Effects of delta subtype-selective ligands (naltrindole, naltriben, tan-67, 7-benzylidene naltrexone) were measured on ethanol consumption in C57BL/6 wildtype and opioid receptor knockout mice using a limited access two-bottle choice paradigm. Affinity and efficacy of naltriben, 7-benzylidenenaltrexone and tan-67 was measured in vitro using radioligand binding and Ca(2+)-mobilizationa assays.
We show that the subtypes of the delta receptor, delta(1) and delta(2), have opposing effects on ethanol consumption. We find that these effects are synergistic; thereby suggesting that delta(1) and delta(2) receptors are distinct molecular targets. Indeed, we provide both in vitro as well as in vivo evidence that the delta(1) subtype is a micro-delta heterodimer and that the delta(2) subtype is most likely a delta homomer.
Together these data provide insight into the limited actions of the clinically important drug naltrexone and identify a novel target with improved specificity and efficacy for the development of new therapeutics for the treatment of alcoholism.
阿片受体是疼痛和酒精滥用的临床重要靶点。已经克隆了三种阿片受体：μ、δ和 κ，它们都能影响动物模型中的酒精消耗。纳曲酮是一种用于治疗酒精中毒的非选择性阿片受体拮抗剂，但其临床疗效受到疗效差和不良反应多的限制。在这里，我们证明纳曲酮治疗的局限性可能反映了其选择性差。尽管经过几十年的研究，这些受体的药理学仍然存在一些谜团。例如，体内存在两种药理学上定义的 δ 受体亚型。
使用有限访问双瓶选择范式，在 C57BL/6 野生型和阿片受体敲除小鼠中，测量 δ 亚型选择性配体（naltrindole、naltriben、tan-67、7-苄基纳曲酮）对乙醇消耗的影响。使用放射性配体结合和 Ca(2+)-动员测定法，在体外测量 naltriben、7-苄基纳曲酮和 tan-67 的亲和力和效力。
我们表明，δ 受体的亚型 δ(1)和 δ(2)对乙醇消耗有相反的影响。我们发现这些影响具有协同作用；从而表明 δ(1)和 δ(2)受体是不同的分子靶点。事实上，我们提供了体外和体内证据，表明 δ(1)亚型是微 δ 异二聚体，而 δ(2)亚型很可能是 δ 同源体。
这些数据共同提供了对临床上重要药物纳曲酮有限作用的深入了解，并确定了一个新的靶标，具有更高的特异性和疗效，可用于开发治疗酒精中毒的新疗法。
