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

Abstract

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.

Synaptic Regulation by OPRM1 Variants in Reward Neurocircuitry

“…1A, 8D-F ). Consistent with our findings, previous studies found that 112G/G mice exhibit a blunted response to morphine/ buprenorphine-induced locomotor activity (Mague et al, 2009;Browne et al, 2017). Moreover, it was found that both male and female G/G mice self-administered more heroin than A/A mice over a 10 d period (Zhang et al, 2015).…”

“…1A). In addition, it has been shown previously that the G allele is associated with an increase in home-cage dominance and increased motivation for nonaggressive social interactions (Briand et al, 2015); and it has also been shown that G-allele carrier mice have attenuated analgesic, anxiolytic, and hyperlocomotive effects from buprenorphine (Browne et al, 2017). In the humanized Oprm1 A118G mouse model, it has been shown that the effects of opioid antagonism on alcohol reward and consumption are affected (Bilbao et al, 2015).…”

“…The A118G SNP is associated with an altered response to drugs of abuse; however, some studies have reported divergent ef- fects (Ray and Hutchison, 2004;Ehlers et al, 2008;Miranda et al, 2010;Koller et al, 2012;Enoch, 2013;Sloan et al, 2018). Significant behavioral differences between the two genotypes have been reported in two mouse models of the A118G SNP: that is, the A112G knock-in and "humanized" A118G mouse models (Mague et al, 2009;Bilbao et al, 2015;Browne et al, 2017). In the A112G mouse model, it was reported that morphine-induced hyperactivity was blunted in G/G mice compared with those in A/A mice (Mague et al, 2009), which we also confirmed in the current study (Fig.…”

“…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).…”

“…Because of the high prevalence of opioid addiction and a high prevalence of the A118G minor allele in human populations (Bergen et al, 1997;Gelernter et al, 1999;Tan et al, 2003;Mague and Blendy, 2010), it is important to gain a more mechanistic and functional understanding of MORs with different SNPs (Lötsch and Geisslinger, 2005) by using mouse (Mague et al, 2009;Bilbao et al, 2015) as well as using human neuronal models (Scarnati et al, 2019). In the rodent model, high heterogeneity of VTA neurocircuitry (Watabe-Uchida et al, 2012;Matsui et al, 2014;Beier et al, 2015) and possible gender-dependent implications (Kanaji et al, 2014;Browne et al, 2017) should be considered. Moreover, given the discrepancy of findings related to A118G SNPs, it is also likely that species-specific-dependent mechanisms are involved; recent developments in human stem cell and human neural stem cell technology (Prytkova et al, 2018;Scarnati et al, 2019) may help facilitate the study of SNPs in a human neuronal context.…”