Reduced expression of the μ opioid receptor in some, but not all, brain regions in mice with OPRM1 A112G.
- Authors
- Wang, Y-J; Huang, P; Ung, A; Blendy, J A; Liu-Chen, L-Y
- Year
- 2012
- Journal
- Neuroscience
- PMID
- 22240251
- DOI
- 10.1016/j.neuroscience.2011.12.033
- PMCID
- PMC3772531
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 [³H]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 [³H]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 [³H]DAMGO binding than G/G mice in more brain regions in males than in females. Radioligand binding using brain membranes also showed higher [³H]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.
Pseudo-color autoradiograms of [3H]DAMGO (~5 nM) binding to the mu opioid receptor in coronal sections of A/A and G/G male mouse brain. Sections were incubated with ~5 nM [3H]DAMGO for 1 h at room temperature, washed, dried, and exposed to tritium-sensitive phosphor screens. Non-specific binding (N.S) was performed in the presence of 10 μM naloxone. Exposure time was 1 wk. The color bars are pseudo-color representation of black and white screen images in nCi/mg tissue equivalents. All the sections were processed in parallel throughout binding experiments and for development of autoradiograms. Abbreviations: cc, cingulate cortex; mc, motor cortex; sc, somatosensory cortex; ic, insular cortex; cpu, caudate putamen; nac, nucleus accumbens; hip, hippocampus; thl, thalamus; hyp, hypothalamus; amg, amygdala; sug, superficial gray of superior colliculus; pag, periaqueductal gray; sn, substantial nigra; vta, ventral tegmental area.
Brain regions that show significant genotype differences in [3H]DAMGO binding level in (A) male and (B) female mice. The data from male and female mice were analyzed separately. Data are the mean±SEM of six animals, two or three sections from each brain. * P<0.05, ** P<0.01, *** P<0.001 different from A/A by the nonpaired two-tailed Student’s t-test.
(A–D) Binding data in Table 2 are separately presented for male and female mice. Data are presented as specific binding/tube (dpm) (mean±SEM, n=4 – 6, each in duplicate). * P<0.05, ** P<0.01 compared with A/A by the nonpaired two-tailed Student’s t-test.
| # | Section | Preview |
|---|---|---|
| 20 | DISCUSSION — Variations in N-glycan types and contents in the two MOPR variants may play a role in region-specific effects of A112G on MOPR protein expression | contents in the MOPR in different brain regions. Importantly, the wild-type MOPR has been shown to… |
| 21 | DISCUSSION — The effects of A112G on MOPR protein expression have sex differences | Our autoradiographic data showed that males exhibited genotype differences in MOPR expression in… |
| 22 | DISCUSSION — The effects of A112G on MOPR protein expression have sex differences | Sex differences in N-linked glycosylation have recently been revealed in total serum proteins in… |
| 23 | DISCUSSION — The effects of A112G on MOPR protein expression have sex differences | is epigenetically programmed in the brain, and methyl-CpG-binding protein 2 (MeCP2) regulates the… |
| 24 | CONCLUSION | Mice with oprm1 A112G, the equivalent of the OPRM1 A118G, exhibited lower MOPR expression in some,… |
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