R. Rijn, Jennifer L. Whistler
Oct 15, 2009
Citations
6
Influential Citations
81
Citations
Quality indicators
Journal
Biological Psychiatry
Abstract
Background Opioid receptors are clinically important targets for both pain and alcohol abuse. Three opioid receptors have been cloned: μ, δ, and κ, 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 δ receptors exist in vivo. Methods Effects of δ 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. Results We show that the subtypes of the δ receptor, δ 1 and δ 2 , have opposing effects on ethanol consumption. We find that these effects are synergistic; thereby suggesting that δ 1 and δ 2 receptors are distinct molecular targets. Indeed, we provide both in vitro as well as in vivo evidence that the δ 1 subtype is a μ-δ heterodimer and that the δ 2 subtype is most likely a δ 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.