The delta(1) opioid receptor is a heterodimer that opposes the actions of the delta(2) 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 Ca(2+)-mobilizationa assays.


RESULTS
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.


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.
van Rijn
Richard M
RM
Ernest Gallo Clinic and Research Center, Department of Neurology, University of California, San Francisco, Emeryville, California 94608, USA.
Whistler
Jennifer L
JL
D000428:Alcohol Drinking / Q000097:blood* / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D002755:Choice Behavior / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009292:Narcotic Antagonists / Q000494:pharmacology; D055503:Protein Multimerization / Q000502:physiology*; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
C470381:DOR-1 protein, mouse; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu