Chronic Ethanol Consumption Reduces δ-and μ-Opioid Receptor-Stimulated G-Protein Coupling in Rat Brain

: Background: Ethanol consumption is thought to enhance the release of endogenous opioids acting at opioid receptors (ORs) in the central nervous system. Prior studies have shown that chronic ethanol consumption in alcohol‐preferring rats uncouples μ‐ORs from Gi proteins. The purpose of this study was to investigate the potential for uncoupling of the δ‐ and the μ‐OR after chronic ethanol consumption in a nonpreferring rat strain. Methods: We used radiohistochemical methods to study μ‐ and δ‐OR‐stimulated G‐protein coupling in brain tissue of rats ingesting liquid diets containing 6.7% ethanol (v/v) for 16 days, as compared with 0% ethanol pair‐fed control rats. Sections of brain from pair‐fed and ethanol‐treated rats were incubated with guanylyl 5′‐[gamma‐[35S]‐thio]‐triphosphate ([35S]‐GTPγS) in the absence and presence of d‐Pen2,d‐Pen5 enkephalin (DPDPE), a δ‐OR agonist, or Tyr‐d‐Ala‐Gly‐N (me)Phe‐Gly‐ol‐enkephalin (DAMGO), a μ‐OR agonist. Results: DPDPE significantly stimulated [35S]‐GTPγS binding in the hippocampal dentate gyrus (DG), CA1, cerebellum, and inferior colliculus of untreated pair‐fed controls. By contrast, DPDPE‐stimulated [35S]‐GTPγS binding was reduced significantly in those brain regions in the ethanol‐consuming group. DAMGO stimulated [35S]‐GTPγS binding in cortex, caudate, nucleus accumbens, DG, CA1, and superior and inferior colliculi, whereas the DG, CA1, and colliculi showed a significant reduction of binding after chronic ethanol. Basal [35S]‐GTPγS binding was not different between the two diet groups. Conclusions: These data are the first to demonstrate functional uncoupling of δ‐ORs from G proteins after chronic ethanol consumption. Uncoupling may result from modulation of receptors, possibly by internalization or phosphorylation. Alterations in functional coupling of both δ‐ and μ‐ORs and subsequent effects may contribute to continued ethanol consumption.