Reduced expression of the mu opioid receptor in some, but not all, brain regions in mice with OPRM1 A112G

Abstract OPRM1 A118G is a common single nucleotide polymorphism (SNP) in the coding region of the human mu opioid receptor (MOPR) gene OPRM1 . This SNP is associated with higher morphine doses required for postoperative analgesia as well as a variety of drug addiction phenotypes. A mouse model posse...

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Bibliographic Details
Published in:Neuroscience 2012-03, Vol.205, p.178-184
Main Authors: Wang, Y.-J, Huang, P, Ung, A, Blendy, J.A, Liu-Chen, L.-Y
Format: Article
Language:English
Subjects:
A118G
Alanine - genetics
Amino Acid Substitution - drug effects
Amino Acid Substitution - genetics
Analgesics, Opioid - pharmacology
Animals
autoradiography
Biological and medical sciences
Disease Models, Animal
Down-Regulation - drug effects
Down-Regulation - genetics
Female
Fundamental and applied biological sciences. Psychology
Gene Knock-In Techniques
Glycine - genetics
Humans
knock-in mouse
Male
Mice
Mice, Inbred C57BL
mu opioid receptor
N-glycosylation
Neurology
Polymorphism, Single Nucleotide - drug effects
Polymorphism, Single Nucleotide - genetics
Receptors, Opioid, mu - antagonists & inhibitors
Receptors, Opioid, mu - biosynthesis
Receptors, Opioid, mu - genetics
Transgenes - drug effects
Transgenes - genetics
Vertebrates: nervous system and sense organs
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Summary:Abstract OPRM1 A118G is a common single nucleotide polymorphism (SNP) in the coding region of the human mu opioid receptor (MOPR) gene OPRM1 . This SNP is associated with higher morphine doses required for postoperative analgesia as well as a variety of drug addiction phenotypes. A mouse model possessing the equivalent substitution (A112G) in the Oprm1 gene was generated to facilitate mechanistic studies. Mice homozygous for the G112 allele (G/G) displayed lower antinociception to morphine compared with those homozygous for A112 allele (A/A), similar to humans, suggesting that the mice are a good model to further characterize underlying factors contributing to phenotypes associated with this SNP. Here, we compared [3 H]DAMGO binding to the MOPR in the brains of A/A and G/G mice using quantitative in vitro autoradiography. A/A mice exhibited higher [3 H]DAMGO binding than G/G in the cingulate, motor, and insular cortices, nucleus accumbens core and shell, hypothalamus, thalamus, amygdala, periaqueductal gray, superficial gray of superior colliculus, and ventral tegmental area. No genotype differences were observed in somatosensory cortex, caudate putamen, and hippocampus. When males and females were examined separately, A/A mice showed higher [3 H]DAMGO binding than G/G mice in more brain regions in males than in females. Radioligand binding using brain membranes also showed higher [3 H]DAMGO binding in the cortex and thalamus in A/A mice than G/G mice but no genotype differences in the caudate putamen or hippocampus. Thus, the A112G SNP is associated with reduced MOPR expression in some, but not all, brain regions, and appears to have some sex differences. The elevated MOPR expression in periaqueductal gray and thalamus in A/A mice are consistent with their higher antinociceptive responses to morphine. The higher MOPR levels in nucleus accumbens and/or ventral tegmental area of A/A mice is consistent with the higher morphine-induced hyperactivity and locomotor sensitization observed in these mice. Thus, these results provide some insights into the observed decreased clinical opioid potency in humans with the A118G SNP.
ISSN:0306-4522
1873-7544
DOI:10.1016/j.neuroscience.2011.12.033