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Psychopharmacology (Berl). 2013 Jul;228(2):207-15. doi: 10.1007/s00213-013-3023-y. Epub 2013 Feb 22.

Effect of chronic ethanol treatment on μ-opioid receptor function, interacting proteins and morphine-induced place preference.

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Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.



Both the acute and chronic consumption of ethanol have been reported to modify several molecular events in the central nervous system, and the endogenous μ-opioid receptor system is involved in the reinforcing/rewarding effects of ethanol.


The present study was designed to clarify the effects of chronic ethanol treatment on cellular processes involving μ-opioid receptor and the development of morphine-induced rewarding effects.


Male C57BL/6J mice were continuously treated with a liquid diet containing 3.0 w/v ethanol. The direct involvement of μ-opioid receptor functions in the activation of G-proteins and changes in protein levels in the lower midbrain of mice after chronic treatment with ethanol were investigated by a [(35)S] GTPγS binding assay and Western blotting, respectively. The rewarding effects of morphine (5 mg/kg) under treatment with ethanol were measured by the conditioned place preference paradigm.


The function of μ-opioid receptor was increased by treatment with ethanol in the lower midbrain using [(35)S] GTPγS binding assay. Furthermore, the GRK2 protein level was significantly increased by treatment with ethanol. Chronic treatment with ethanol enhanced the rewarding effects of morphine. On the other hand, this enhancement of the rewarding effects of morphine by ethanol treatment was significantly inhibited by the GRK2 inhibitor β-adrenergic receptor kinase 1 inhibitor.


The present study demonstrated that chronic treatment with ethanol enhanced the rewarding effects of morphine by up-regulating functional changes in μ-opioid receptor, mediated by GRK2.

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