Brain region- and sex-specific alterations in DAMGO-stimulated [35S]GTPγS binding in mice with Oprm1 A112G

The A118G single nucleotide polymorphism (SNP) of the human mu-opioid receptor (MOPR) gene (OPRM1) was associated with heightened dopamine release by alcohol intake, better treatment outcome for nicotine and alcohol addiction, and reduced analgesic responses to morphine. A mouse model that possesses the equivalent substitution (A112G) in the mouse MOPR gene (OPRM1) was generated to delineate the mechanisms of the impact of the SNP. Mice homozygous for the G112 allele (G/G) displayed lower morphine-induced antinociception than mice homozygous for the A112 allele (A/A), similar to the results in humans. In this study, we examined whether A112G SNP affected MOPR-mediated G protein activation in the mouse model. We compared A/A and G/G mice in the MOPR-selective agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO)-stimulated [S-35]GTP gamma S binding in brain regions by autoradiography. When the data of males and females were combined, G/G mice exhibited lower DAMGO-stimulated [S-35]GTP gamma S binding in the ventral tegmental area than A/A mice, in accord with the previously reported reduced morphine-induced hyperactivity and locomotor sensitization in G/G mice. In the nucleus accumbens (NAc) core, female G/G mice displayed lower DAMGO-stimulated [S-35]GTP gamma S binding than female A/A mice, which is consistent with the previously reported deficiency in morphine-induced conditioned place preference in female G/G mice. In G/G mice, males showed higher DAMGO-stimulated [S-35]GTP gamma S binding than females in the cingulate cortex, caudate putamen, NAc core, thalamus and amygdala. Thus, A112G SNP affects DAMGO-stimulated [S-35]GTP gamma S binding in region- and sex-specific manners.