Mouse model of OPRM1 (A118G) polymorphism has sex-specific effects on drug-mediated behavior.
Journal:
Proc. Natl. Acad. Sci. U.S.A. 2009 JunAuthors:
Mague SD, Isiegas C, Huang P, Liu-Chen LY, Lerman C, Blendy JA
Abstract
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
...[more] 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.[less]
Mesh Headings:
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