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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

Authors

  • Mague SD
  • Isiegas C
  • Huang P
  • Liu-Chen LY
  • Lerman C
  • Blendy JA

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

June 30, 2009

Associated Grants

  • Agency: NIDA NIH HHS, Id: P30 DA013429
  • Agency: NIDA NIH HHS, Id: P30-DA-13429
  • Agency: NCI NIH HHS, Id: P50-CA-084718
  • Agency: NIDA NIH HHS, Id: R01 DA017302
  • Agency: NIDA NIH HHS, Id: R01-DA-011649
  • Agency: NIDA NIH HHS, Id: R01-DA-17302
  • Agency: NIDA NIH HHS, Id: R21 DA027066
  • Agency: NIDA NIH HHS, Id: T32-DA-007241-15

Mesh Terms

  • 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