Oprm1 A112G, a single nucleotide polymorphism, alters expression of stress-responsive genes in multiple brain regions in male and female mice

Abstract

BackgroundOPRM1 A118G, a functional human mu-opioid receptor (MOR) polymorphism, is associated with drug dependence and altered stress responsivity in humans as well as altered MOR signaling. MOR signaling can regulate many cellular processes, including gene expression, and many of the long-term, stable effects of drugs and stress may stem from changes in gene expression in diverse brain regions. A mouse model bearing an equivalent polymorphism (Oprm1 A112G) was previously generated and studied. Mice homozygous for the G112 allele show differences in opioid- and stress-related phenotypes.ApproachThe current study examines the expression of 24 genes related to drug and stress responsivity in the caudoputamen, nucleus accumbens, hypothalamus, hippocampus, and amygdala of drug-naïve, stress-minimized, male and female mice homozygous for either the G112 variant allele or the wild-type A112 allele.ResultsWe detected nominal genotype-dependent changes in gene expression of multiple genes. We also detected nominal sex-dependent as well as sex-by-genotype interaction effects on gene expression. Of these, four genotype-dependent differences survived correction for multiple testing: Avp and Gal in the hypothalamus and Oprl1 and Cnr1 in the hippocampus.ConclusionsChanges in the regulation of these genes by mu-opioid receptors encoded by the G112 allele may be involved in some of the behavioral and molecular consequences of this polymorphism observed in mice.

Neurobehavioral effects of neonatal opioid exposure in mice: Influence of the OPRM1 SNP

“…Previous work from our lab demonstrate that both male and female GG animals exhibit decreased MOR mRNA expression and protein levels compared to AA animals, and this is associated with reduced locomotor response to opioids 6,8. A recent study investigating baseline mRNA expression levels of drug-and stress-related genes in A112G mice found that hypothalamic expression of the neuropeptides arginine vasopressin (Avp) and galanin (Gal), and hippocampal expression of the opioid-related nociception receptor (Oprl1) and cannabinoid receptor 1 (Cnr1) were significantly reduced in animals with the G allele (Collins 2018). Thus, the influence of the Oprm1 SNP in these studies may be due to differential expression of opioid receptors and/or an attenuation of MOR-mediated transcriptional regulation.…”

Binge-Like Eating Is Not Influenced by the Murine Model of OPRM1 A118G Polymorphism

“…Notably, in a longitudinal 4-year familial study of mothers ( n = 2,460) and children ( n = 3,720), there was no association of the G allele with body mass index (BMI) or waist circumference (Hardman et al., 2014). It has been demonstrated, however, that GG mice show a reduction in hypothalamic gene expression AVP (arginine vasopressin) and Gal (galanin) (Collins et al., 2018). Additionally, it is possible, as our results suggest, that mice with the A112G variant have impairments in body weight compensation following repeated bouts of intermittent calorie deprivation.…”

Genetic Vulnerability to Opioid Addiction

“…We have further characterized the heterozygous mice, 112AA versus 112GG, investigating differences in baseline (opioid-naive) gene expression of several genes that interact with the endogenous opioid system in diverse brain regions of adult mice (Collins et al 2018). We found several gene expression alterations, most strongly the expression levels of the precursors of the neuropeptides arginine vasopressin and galanin in the hypothalamus and the expression of opioid receptor-like receptor (ORL1; target of orphanin FQ/nociceptin peptide) and cannabinoid receptor type 1 (CB 1 ) in the hippocampus.…”