The δ1 Opioid Receptor Is a Heterodimer That Opposes the Actions of the δ2 Receptor on Alcohol Intake

Background: 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. Methods: 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 Ca2+-mobilizationa assays. Results: We show that the subtypes of the 8 receptor, 8, and 6, have opposing effects on ethanol consumption. We find that these effects are synergistic; thereby suggesting that 8, and 82 receptors are distinct molecular targets. Indeed, we provide both in vitro as well as in vivo evidence that the delta(1) subtype is a mu-delta heterodimer and that the 62 subtype is most likely a 8 homomer. Conclusions: 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.