Mouse model of OPRM1 (A118G) polymorphism has sex-specific effects on drug-mediated behavior.
A single nucleotide polymorphism (SNP) in the human mu-opioid receptor gene (OPRM1 A118G) has been widely studied for its association in a variety of drug addiction and pain sensitivity phenotypes; however, the extent of these adaptations and the mechanisms underlying these associations remain elusive. To clarify the functional mechanisms linking the OPRM1 A118G SNP to addiction and analgesia phenotypes, we derived a mouse model possessing the equivalent nucleotide/amino acid substitution in the Oprm1 gene. Mice harboring this SNP (A112G) demonstrated several phenotypic similarities to humans carrying the A118G SNP, including reduced mRNA expression and morphine-mediated antinociception. We found additional phenotypes associated with this SNP including significant reductions of receptor protein levels, morphine-mediated hyperactivity, and the development of locomotor sensitization in mice harboring the G112 allele. In addition, we found sex-specific reductions in the rewarding properties of morphine and the aversive components of naloxone-precipitated morphine withdrawal. Further cross-species analysis will allow us to investigate mechanisms and adaptations present in humans carrying this SNP.
Pubmed ID: 19528658 RIS Download
Analgesics, Opioid | Animals | Base Sequence | Binding, Competitive | Conditioning, Operant | Enkephalin, Ala(2)-MePhe(4)-Gly(5)- | Female | Gene Expression | Gene Frequency | Genotype | Humans | Male | Mice | Mice, Inbred C57BL | Models, Animal | Morphine | Motor Activity | Pain | Pain Measurement | Polymorphism, Single Nucleotide | RNA, Messenger | Receptors, Opioid, mu | Reverse Transcriptase Polymerase Chain Reaction | Sex Factors | Substance Withdrawal Syndrome