The link between endogenous opioid peptides and the genetic predisposition to preferentially consume ethanol was examined in alcohol preferring C57BL/6J mice compared with the alcohol nonpreferring DBA/2 mice. Concentrations of Met‐enkephalin pentapeptide or precursor in various brain regions of potential relevance were not different between the two strains. C57BL/6J mice had a significantly lower pain threshold that could be increased by a selective mu‐receptor opioid agonist D‐Ala2, MePhe4, Met(0)5‐ol‐enkephalin. Treatment with this drug also decreased ethanol consumption in C57BL/6J mice. Increasing the synaptic half‐life of endogenous enkephalins by the enkephalinase inhibitor kelatorphan also decreased ethanol consumption. Assay of endogenous enkephalin degrading activity showed increased enkephalinase activity in striatal issue of C57BL/6J compared with DBA/2 tissue. These results suggest that a relative lack of enkephalin peptides trans‐synaptically, possibly resulting from enhanced enkephalin degradation may contribute to increase alcohol consumption in
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