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.
Mague
Stephen D
SD
Department of Pharmacology, Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Isiegas
Carolina
C
Huang
Peng
P
Liu-Chen
Lee-Yuan
LY
Lerman
Caryn
C
Blendy
Julie A
JA
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D001667:Binding, Competitive; D003216:Conditioning, Operant / Q000187:drug effects; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009020:Morphine / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D010146:Pain / Q000503:physiopathology / Q000517:prevention & control; D010147:Pain Measurement / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012737:Sex Factors; D013375:Substance Withdrawal Syndrome / Q000235:genetics
D000701:Analgesics, Opioid; C404943:Oprm protein, mouse; D012333:RNA, Messenger; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009020:Morphine