Increased ethanol drinking in "humanized" mice expressing the mu opioid receptor A118G polymorphism are mediated through sex-specific mechanisms.

The A118G single nucleotide polymorphism (SNP) of the mu-opioid receptor gene (Oprm1) has been implicated in mediating the rewarding effects of alcohol. Clinical and preclinical studies suggest that the G allele may confer a genetic vulnerability to alcohol dependence, though it remains unknown whether these effects are sex-specific. We used male and female mice homozygous for the "humanized" 118AA or 118GG alleles to determine whether the A118G SNP potentiates ethanol consumption in a sex-specific manner in both the two-bottle choice and drinking-in-the-dark (DID) paradigms. Mice were also assessed for differences in naltrexone sensitivity, ethanol reward assessed via conditioned place preference (CPP), and sensitivity to the sedative/ataxic effects of ethanol using the rota-rod and loss of righting reflex (LORR) assays. We found that male and female 118GG mice drank significantly more ethanol than 118AA littermates using a continuous access, two-bottle choice paradigm. In the limited-access DID drinking model, (i) female (but not male) 118GG mice consumed more ethanol than 118AA mice and (ii) naltrexone pretreatment was equally efficacious at attenuating ethanol intake in both 118AA and 118GG female mice while having no effect in males. Male and female 118GG and female 118AA mice developed a robust conditioned place preference (CPP) for ethanol. Female 118GG mice displayed less sensitivity to the sedative/ataxic effects of ethanol compared to female 118AA mice on both the rota-rod and the LORR assays while male mice did not differ in their responses on either assay. Our findings suggest that increased ethanol consumption in male 118GG mice may be due to increased ethanol reward, while increased drinking in female 118GG mice might be due to decreased sensitivity to the sedative/ataxic effects of ethanol. Collectively, these data might be used to help identify sex-specific pharmacotherapies to combat alcohol use disorders.

Morphine-induced antinociception and reward in "humanized" mice expressing the mu opioid receptor A118G polymorphism.

The rewarding and antinociceptive effects of opioids are mediated through the mu-opioid receptor. The A118G single nucleotide polymorphism in this receptor has been implicated in drug addiction and differences in pain response. Clinical and preclinical studies have found that the G allele is associated with increased heroin reward and self-administration, elevated post-operative pain, and reduced analgesic responsiveness to opioids. Male and female mice homozygous for the "humanized" 118AA or 118GG alleles were evaluated to test the hypothesis that 118GG mice are less sensitive to the rewarding and antinociceptive effects of morphine. We found that 118AA and 118GG mice of both genders developed conditioned place preference for morphine. All mice developed tolerance to the antinociceptive and hypothermic effects of morphine. However, morphine tolerance was not different between AA and GG mice. We also examined sensitivity to the antinociceptive and hypothermic effects of cumulative morphine doses. We found that 118GG mice show reduced hypothermic and antinociceptive responses on the hotplate for 10mg/kg morphine. Finally, we examined basal pain response and morphine-induced antinociception in the formalin test for inflammatory pain. We found no gender or genotype differences in either basal pain response or morphine-induced antinociception in the formalin test. Our data suggests that homozygous expression of the GG allele in mice blunts morphine-induced hypothermia and hotplate antinociception but does not alter morphine CPP, morphine tolerance, or basal inflammatory pain response.