Brain region- and sex-specific alterations in DAMGO-stimulated [(35) S]GTPγS binding in mice with Oprm1 A112G.
- Authors
- Wang, Yu-Jun; Huang, Peng; Blendy, Julie A; Liu-Chen, Lee-Yuan
- Year
- 2014
- Journal
- Addiction biology
- PMID
- 22862850
- DOI
- 10.1111/j.1369-1600.2012.00484.x
- PMCID
- PMC3864546
The A118G single nucleotide polymorphism (SNP) of the human μ-opioid receptor (MOPR) gene (OPRM1) was associated with heightened dopamine release by alcohol intake, better treatment outcome for nicotine and alcohol addiction, and reduced analgesic responses to morphine. A mouse model that possesses the equivalent substitution (A112G) in the mouse MOPR gene (OPRM1) was generated to delineate the mechanisms of the impact of the SNP. Mice homozygous for the G112 allele (G/G) displayed lower morphine-induced antinociception than mice homozygous for the A112 allele (A/A), similar to the results in humans. In this study, we examined whether A112G SNP affected MOPR-mediated G protein activation in the mouse model. We compared A/A and G/G mice in the MOPR-selective agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO)-stimulated [(35) S]GTPγS binding in brain regions by autoradiography. When the data of males and females were combined, G/G mice exhibited lower DAMGO-stimulated [(35) S]GTPγS binding in the ventral tegmental area than A/A mice, in accord with the previously reported reduced morphine-induced hyperactivity and locomotor sensitization in G/G mice. In the nucleus accumbens (NAc) core, female G/G mice displayed lower DAMGO-stimulated [(35) S]GTPγS binding than female A/A mice, which is consistent with the previously reported deficiency in morphine-induced conditioned place preference in female G/G mice. In G/G mice, males showed higher DAMGO-stimulated [(35) S]GTPγS binding than females in the cingulate cortex, caudate putamen, NAc core, thalamus and amygdala. Thus, A112G SNP affects DAMGO-stimulated [(35) S]GTPγS binding in region- and sex-specific manners.
Autoradiograms of DAMGO-stimulated [35S]GTPγS binding in selected coronal sections of male A/A mouse brains at the telencephalon (A), diencephalon (B) and midbrain (C) levelsSections were incubated with ~0.04 nM [35S]GTPγS and 2 mM GDP in the absence (basal) or presence of 10 µM DAMGO for 2 hr at 25°C, washed, dried, and exposed to phosphor screens for 48 hr. Abbreviation: cc, cingulate cortex; mc, motor cortex; sc, somatosensory cortex; ic, insular cortex; cpu, caudate putamen; acb, nucleus accumbens; hpc, hippocampus; hyp, hypothalamus; thl, thalamus; amg, amygdala; pag, periaqueductal gray; sn, substantial nigra; sug, superficial grey of superior colliculus; vta, ventral tegmental area.
Pseudo-color autoradiograms of DAMGO-stimulated [35S]GTPγS binding to the MOPR in selected coronal sections of A/A and G/G male mouse brains at 3 anatomical levels (A–C)Experiments were carried out as described in Fig. 1 legend.
Brain regions that show significant sex differences in DAMGO-stimulated [35S]GTPγS binding in G/G miceData are expressed at mean ± S.E.M. of five to six animals, three or four sections from each brain. *p < 0.05 different from G/G male by the non-paired two-tailed Student’s t test.
In the nucleus accumbens core, there is significant genotype difference in DAMGO-stimulated [35S]GTPγS binding in female miceData are expressed at mean ± S.E.M. of five to six animals, three or four sections from each brain. *p < 0.05, **p < 0.01 different from A/A female by the non-paired two-tailed Student’s t test.
| # | Section | Preview |
|---|---|---|
| 20 | Discussion — Regional differences in basal [35S]GTPγS binding | In addition, there is a marked variation in basal [35S]GTPγS binding across different brain… |
| 21 | Discussion — Regional differences in basal [35S]GTPγS binding | In summary, A112G affected DAMGO-stimulated [35S]GTPγS binding in region- and sex-specific manners.… |
| Name | Type |
|---|---|
| [14C] local | drug |
| [14C]microscales local | drug |
| [14C] standards local | drug |
| [35S]GTPγS local | drug |
| [35S]GTPγS binding local | drug |
| [35S]GTPγS binding local | phenotype |
| [3H]DAMGO | drug |
| A112 allele local | variant |
| A112G local | variant |
| A112G mice local | cohort |
| A112G-MOPR local | variant |
| A112G-MOPR knock-in mice local | cohort |
| A112G SNP local | variant |
| A118G SNP | variant |
| A118 homozygotes local | cohort |
| A118 mice local | cohort |
| A/A local | variant |
| A allele genotype local | variant |
| A/A mice local | cohort |
| absence of conditioned place preference to morphine local | phenotype |
| Acute postoperative pain local | phenotype |
| African American | cohort |
| agonist | drug |
| alcohol | phenotype |
| alcohol dependence | phenotype |
| Alcohol dependent patients treated with naltrexone local | cohort |
| amygdala | anatomy |
| Asian | cohort |
| basal [35S]GTPγS binding local | phenotype |
| basal binding local | phenotype |
| brain | anatomy |
| brain paste standard assay local | drug |
| C57BL/6J | cohort |
| Carriers of the G118 allele local | cohort |
| Caucasians | cohort |
| cingulate cortex | anatomy |
| conditioned place preference | phenotype |
| cortex | anatomy |
| Cyclone Storage Phosphor Scanner local | drug |
| DAMGO | drug |
| DAMGO-stimulated [35S]GTPγS binding local | phenotype |
| dopamine release | drug |
| dorsal striatum | anatomy |
| EGTA | drug |
| female G/G mice local | cohort |
| female mice | cohort |
| G112 allele local | variant |
| G118 mice local | cohort |
| G allele genotype local | variant |
| GDP | drug |
| G/G local | variant |
| G/G mice local | cohort |
| greater peak dopamine response to alcohol local | phenotype |
| GTPγS local | drug |
| H2O local | drug |
| higher [3H]DAMGO binding local | phenotype |
| Higher morphine dose requirement local | phenotype |
| Hispanic | phenotype |
| hyperactivity | phenotype |
| hypothalamus | anatomy |
| Individuals using transdermal nicotine for smoke cessation local | cohort |
| locomotor sensitization | phenotype |
| male A/A mice local | cohort |
| male G/G mice local | cohort |
| male mice | cohort |
| MgCl2 | drug |
| MOPR local | gene |
| MOPR expression local | phenotype |
| MOPR-G protein coupling local | phenotype |
| MOPR N-glycosylation local | phenotype |
| MOPR protein stability local | phenotype |
| morphine | drug |
| Morphine-induced antinociception local | phenotype |
| morphine-induced pharmacological effects local | phenotype |
| NAc | anatomy |
| NAc core | anatomy |
| naltrexone | drug |
| nCi/g local | drug |
| NDPK local | gene |
| net DAMGO-stimulated [35S]GTPγS binding local | phenotype |
| nicotine | drug |
| nicotine patch | drug |
| nucleus accumbens | anatomy |
| OPRM1 | cohort |
| OPRM1 A112G local | variant |
| OPRM1 A118G | cohort |
| OPRM1 N38D local | variant |
| OptiQuant program local | drug |
| Other populations local | cohort |
| outcome | phenotype |
| PAG local | anatomy |
| phosphor screens local | drug |
| present study mice local | cohort |
| Ramchandani 2011 mice local | cohort |
| reduced antinociceptive response to morphine local | phenotype |
| reduced locomotor sensitization local | phenotype |
| reduced morphine-induced hyperactivity local | phenotype |
| reduced morphine potency on Ca2+ channels in sensory neurons local | phenotype |
| rs1799971 | variant |
| sex | phenotype |
| sex-specific protein expression local | phenotype |
| Smoking cessation response local | phenotype |
| substantia nigra | anatomy |
| superficial layers of the superior colliculus local | anatomy |
| superior colliculus superficial layers local | anatomy |
| thalamus | anatomy |
| Tris-HCl | drug |
| VTA | anatomy |
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