Receptor Reserve Moderates Mesolimbic Responses to Opioids in a Humanized Mouse Model of the OPRM1 A118G Polymorphism

Robinson, J. Elliott; Vardy, Eyal; DiBerto, Jeffrey F.; Chefer, Vladimir I.; White, Kate L.; Fish, Eric W.; Chen, Meng; Gigante, Eduardo D.; Krouse, Michael C.; Sun, Hui; Thorsell, Annika; Roth, Bryan L.; Heilig, Markus; Malanga, C. J.

doi:10.1038/npp.2015.109

Cited by 29 publications

(17 citation statements)

References 47 publications

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“…Conversely, in HEK239 cells, no effect of genotype was observed on suppression of Ca 2+ channel inhibition following BPN administration (Robinson et al, 2015). These contradictory findings may be a result of cell specific differences in Gα and βγ subunits, that mask genotype dependent changes in BPN mediated second messenger coupling.…”

Section: Discussionmentioning

confidence: 99%

“…In a complimentary approach, a different mouse line was generated that express humanized receptors with and without the A118G variant (Ramchandani et al, 2011). The effects of morphine but not fentanyl on intracranial self-stimulation and dopamine release in the nucleus accumbens were blunted in the humanized mouse model of the OPRM1 A118G polymorphism (Robinson et al, 2015). Using the same model, trigeminal ganglion neurons isolated from mice with the G allele exhibited blunted inhibition of Ca 2+ channels following morphine but not fentanyl administration ex vivo (Mahmoud et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Genetic variation in the behavioral effects of buprenorphine in female mice derived from a murine model of the OPRM1 A118G polymorphism

et al. 2017

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Pharmacogenetic studies have identified the non-synonymous single nucleotide polymorphism (A118G) in the human mu opioid receptor (MOR) gene (OPRM1) as a critical genetic variant capable of altering the efficacy of opioid therapeutics. To date few studies have explored the potential impact of the OPRM1 A118G polymorphism on the pharmacological effects of buprenorphine (BPN), a potent MOR partial agonist and kappa opioid receptor antagonist, which is approved by the FDA for the treatment of opioid addiction and chronic pain. The goal of these studies was to determine whether the MOR-mediated behavioral effects of BPN were altered in the Oprm1 A112G mouse model of the human OPRM1 A118G SNP. All studies were conducted in female, AA, AG and GG mice. BPN’s maximal analgesic effect in the hot plate test was significantly blunted in AG and GG mice compared to wild type AA mice. Similarly, the BPN-induced reduction of latency to consume food in the novelty induced hypophagia test was blocked entirely in AG and GG mice compared to their AA littermates. In addition, GG mice exhibited marked reductions in psychostimulant hyperlocomotor activity compared to the AA group. In contrast, reduced immobility in the forced swim test, an effect of BPN mediated by kappa opioid receptors, was not affected by genotype. These studies demonstrate the ability of the Oprm1 A112G SNP to attenuate the analgesic, anxiolytic and hyperlocomotor effects of BPN. Overall, these data suggest that the OPRM1 A118G SNP will significantly impact the clinical efficacy of BPN in its therapeutic applications.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genetic variation in the behavioral effects of buprenorphine in female mice derived from a murine model of the OPRM1 A118G polymorphism

et al. 2017

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“…Another possible explanation for the decreased morphine sensitivity in 118GG mice is that the G allele causes decreased amounts of MOR protein. Previous reports showing that the G allele causes decreased MOR mRNA expression, protein levels, and/or protein stability support this possibility (Zhang et al, 2005; Mague et al, 2009; Huang et al, 2012; Wang et al, 2012; Wang et al, 2014; Robinson et al, 2015). …”

Section: 1 Discussionmentioning

confidence: 82%

“…The use of different genetic models (humanized vs. mouse transgenic) might be responsible for the slight discrepancies between these two studies. However, Robinson and colleagues recently found that humanized male 118GG mice display less morphine-stimulated dopamine release in the nucleus accumbens and decreased morphine reward [assessed using an intra-cranial self-stimulation (ICSS) model] compared to 118AA controls (Robinson et al, 2015). Despite the reduction in dopamine release and morphine reward, transgenic 112GG mice self-administer more heroin than 112AA mice (Zhang et al, 2015).…”

Section: 1 Discussionmentioning

confidence: 99%

Morphine-induced antinociception and reward in “humanized” mice expressing the mu opioid receptor A118G polymorphism

Henderson-Redmond

Yuill

Lowe

et al. 2016

Brain Research Bulletin

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The rewarding and antinociceptive effects of opioids are mediated through the mu-opioid receptor. The A118G single nucleotide polymorphism in this receptor has been implicated in drug addiction and differences in pain response. Clinical and preclinical studies have found that the G allele is associated with increased heroin reward and self-administration, elevated post-operative pain, and reduced analgesic responsiveness to opioids. Male and female mice homozygous for the "humanized" 118AA or 118GG alleles were evaluated to test the hypothesis that 118GG mice are less sensitive to the rewarding and antinociceptive effects of morphine. We found that 118AA and 118GGmice of both genders developed conditioned place preference for morphine. All mice developed tolerance to the acute antinociceptive and hypothermic effects of morphine. However, morphine tolerance was not different between AA and GG mice. We also examined sensitivity to the acute antinociceptive and hypothermic effects of cumulative morphine doses. We found that 118GG mice show reduced hypothermic and antinociceptive responses on the hotplate for 10 mg/kg morphine. Finally, we examined basal pain response and morphine-induced antinociception in the formalin test for inflammatory pain. We found no gender or genotype differences in either basal pain response or morphine-induced antinociception in the formalin test. Our data suggests that homozygous expression of the GG allele in mice blunts morphine-induced hypothermia and hotplate antinociception but does not alter morphine CPP, morphine tolerance, or basal inflammatory pain response. *Corresponding Authors: Daniel J Morgan, Department of Anesthesiology, Penn State University College of Medicine, Mailcode H187, Room C2850, 500 University Drive, Hershey, PA 17033, Phone: (717) 531-0003 x283824, ; Email: dmorgan1@hmc.psu.edu; JoséeGuindon, Department of Pharmacology and Neuroscience, Texas Tech University Health Science Center, 3601 4th Street STOP 6592, Lubbock, TX 79430, Phone: (806) ; Email: josee.guindon@ttuhsc.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access IntroductionChronic pain is a highly prevalent and expensive public health condition that afflicts over 100 million Americans and costs society in excess of $635 billion annually ( Gaskin and Richard, 2012 ). Chronic pain generally, although not exclusively, arises from previously experienced unrelieved acute pain, and for both, opiates are frequently prescribed. Concomitant with the rise in physician-prescribed opiates is a dramatic increase in prescription opiate abuse wh...

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“…A loss of function in the minor allele caused differential outcomes, which might account for the different reward behaviors induced by drugs of abuse ( Fig. 1A) (Ramchandani et al, 2011;Bilbao et al, 2015;Robinson et al, 2015;Zhang et al, 2015;Browne et al, 2017) or other types of behavior (Briand et al, 2015).…”

Section: Impact Of Oprm1 A118 Gene Variant (N40d Mors) On Synaptic Rementioning

confidence: 99%

Synaptic Regulation by OPRM1 Variants in Reward Neurocircuitry

et al. 2019

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Mu-opioid receptors (MORs) are the primary site of action of opioid drugs, both licit and illicit. Susceptibility to opioid addiction is associated with variants in the gene encoding the MOR, OPRM1. Varying with ethnicity, ϳ25% of humans carry a single nucleotide polymorphism (SNP) in OPRM1 (A118G). This SNP produces a nonsynonymous amino acid substitution, replacing asparagine (N40) with aspartate (D40), and has been linked with an increased risk for drug addiction. While a murine model of human OPRM1 A118G (A112G in mouse) recapitulates most of the phenotypes reported in humans, the neuronal mechanisms underlying these phenotypes remain elusive. Here, we investigated the impact of A118G on opioid regulation of synaptic transmission in mesolimbic VTA dopaminergic neurons. Using electrophysiology, we showed that both inhibitory and excitatory inputs to VTA dopaminergic neurons projecting to the NAc medial shell were suppressed by the MOR agonists DAMGO and morphine, which caused a shift in the excitatory/inhibitory balance and an increased action potential firing rate. Mice carrying the 112G/G allele exhibited lower sensitivity to DAMGO and morphine compared with major allele carriers (112A/A). Paradoxically, DAMGO produced facilitatory effects on mEPSCs, which were mediated by presynaptic GABA B receptors. However, this was only prominent in homozygous major allele carriers, which could explain a stronger shift in action potential firing in 112A/A mice. This study provides a better understanding on the neurobiological mechanisms that may underlie risk of addiction development in carriers of the A118G SNP in OPRM1.The pandemic of opioid drug abuse is associated with many socioeconomic burdens. The primary brain target of opioid drugs is the -opioid receptor (MOR), encoded by the OPRM1 gene, which is highly polymorphic in humans. Using a mouse model of the human OPRM1 A118G single nucleotide polymorphism (SNP) (A112G in mice), we demonstrated that MOR and GABA B signaling coordinate in regulating mesolimbic dopamine neuronal firing via presynaptic regulation. The A118G SNP affects MOR-mediated suppression of GABA and glutamate release, showing weaker efficacy of synaptic regulation by MORs. These results may shed light on whether MOR SNPs need to be considered for devising effective therapeutic interventions.

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Receptor Reserve Moderates Mesolimbic Responses to Opioids in a Humanized Mouse Model of the OPRM1 A118G Polymorphism

Cited by 29 publications

References 47 publications

Genetic variation in the behavioral effects of buprenorphine in female mice derived from a murine model of the OPRM1 A118G polymorphism

Genetic variation in the behavioral effects of buprenorphine in female mice derived from a murine model of the OPRM1 A118G polymorphism

Morphine-induced antinociception and reward in “humanized” mice expressing the mu opioid receptor A118G polymorphism

Synaptic Regulation by OPRM1 Variants in Reward Neurocircuitry

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