title: Mouse model of OPRM1 (A118G) polymorphism has altered hippocampal function.
abstract: A single nucleotide polymorphism (SNP) in the human μ-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 altered phenotypes, we used a mouse model possessing the equivalent nucleotide/amino acid substitution in the Oprm1 gene. In order to investigate the impact of this SNP on circuit function, we used voltage-sensitive dye imaging in hippocampal slices and in vivo electroencephalogram recordings of the hippocampus following MOPR activation. As the hippocampus contains excitatory pyramidal cells whose activity is highly regulated by a dense network of inhibitory neurons, it serves as an ideal structure to evaluate how putative receptor function abnormalities may influence circuit activity. We found that MOPR activation increased excitatory responses in wild-type animals, an effect that was significantly reduced in animals possessing the Oprm1 SNP. Furthermore, in order to assess the in vivo effects of this SNP during MOPR activation, EEG recordings of hippocampal activity following morphine administration corroborated a loss-of-function phenotype. In conclusion, as these mice have been shown to have similar MOPR expression in the hippocampus between genotypes, these data suggest that the MOPR A118G SNP results in a loss of receptor function.
authors.affiliation: Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Mague
authors.affiliation: Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Russell G
authors.initials: RG
authors.lastname: Port
authors.affiliation: Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: McMullen
authors.affiliation: Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Greg C
authors.initials: GC
authors.lastname: Carlson
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC 29036, USA. Electronic address: jiturner@sccp.sc.edu.
authors.forename: Jill R
authors.initials: JR
authors.lastname: Turner
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D000069280:Electrocorticography; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D005260:Female; D005838:Genotype; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D020641:Polymorphism, Single Nucleotide; D017450:Receptors, Opioid, mu / Q000235:genetics* / Q000378:metabolism*; D046509:Tissue Culture Techniques; D056969:Voltage-Sensitive Dye Imaging
chemical_list: D000701:Analgesics, Opioid; C404943:Oprm protein, mouse; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
keywords: A112G; A118G; Genotype; Hippocampus; Mice; Mu-opioid receptor; N40D; OPRM1; Sex; Single nucleotide polymorphism