Cocaine-induced suppression of saccharin intake and morphine modulation of Ca2+ channel currents in sensory neurons of OPRM1 A118G mice

Abstract

Several studies have shown that human carriers of the single nucleotide polymorphism of the µ-opioid receptor, OPRM1 A118G, exhibit greater drug and alcohol use, increased sensitivity to pain, and reduced sensitivity to the antinociceptive effects of opiates. In the present study, we employed a ‘humanized’ mouse model containing the wild-type (118AA) or variant (118GG) allele to examine behavior in our model of drug-induced suppression of a natural reward cue and to compare the morphine pharmacological profile in acutely isolated sensory neurons. Compared with 118AA mice, our results demonstrate that homozygous 118GG mice exhibit greater avoidance of the cocaine-paired saccharin cue, a behavior linked to an aversive withdrawal-like state. Electrophysiological recordings confirmed the reduced modulation of Ca2+ channels by morphine in trigeminal ganglion (TG) neurons from 118GG mice compared to the 118AA control cells. However, repeated cocaine exposure in 118GG mice led to a leftward shift of the morphine concentration-response relationship when compared with 118GG control mice, while a rightward shift was observed in 118AA mice. These results suggest that cocaine exposure of mice carrying the 118G allele leads to a heightened sensitivity of the reward system and a blunted modulation of Ca2+ channels by morphine in sensory neurons.

Ceftriaxone attenuates acquisition and facilitates extinction of cocaine-induced suppression of saccharin intake in C57BL/6J mice

“…The data in the current manuscript demonstrate that ceftriaxone delays acquisition of cocaine-induced suppression in C57BL/6J mice (Figure 2). Published literature of suppression in mice (e.g., Freet et al , 2013, Freet et al , 2014, Freet et al , 2009) demonstrates that saline controls and drug groups start with similar saccharin intake on Trial 1. This makes sense, of course, given that drug (or saline) has yet to be experienced on that trial.…”

Heroin-induced suppression of saccharin intake in OPRM1 A118G mice

“…These mice have been reported to exhibit increased responsiveness to alcohol (Bilbao et al, 2015; Ramchandani et al, 2011), increased nicotine self-administration (Bernardi et al, 2016), and decreased morphine-induced antinociception (Henderson-Redmond et al, 2016; Mahmoud et al, 2011). Likewise, we previously have demonstrated that humanized OPRM1 A118G mice exhibit greater avoidance of a cocaine-paired saccharin cue in an animal model of the devaluation of natural rewards by drugs of abuse (Freet et al, 2015). It is well known that rodents will avoid a lesser reward if it predicts the future availability of a more preferred, intense reward (for review, see Flaherty, 1996) and it has been hypothesized that, with taste-drug pairings (e.g., saccharin and cocaine), avoidance of intake of the lesser saccharin reward cue is, at least in part, due to a decrease in the relative value of the taste cue when compared with the potent drug of abuse that is expected in the near future (Grigson, 2002, 1997; Grigson et al, 2009).…”

“…Humanized 118GG mice, then, defend their intake of the sweet cue despite saccharin-heroin pairings and this effect is illuminated by the use of spaced, rather than massed, trials. Given that this pattern of strain difference is not evident with saccharin-cocaine pairings (Freet et al, 2015), reduced avoidance of the heroin-paired saccharin cue by the 118GG mice may be due to an interaction between the opiate and the subjects’ drive for the sweet or, alternatively, to differential downstream sensitivity to the aversive kappa mediated properties of the drug. These alternative hypotheses are addressed.…”

Binge-Like Eating Is Not Influenced by the Murine Model of OPRM1 A118G Polymorphism

“…This substitution strategy at this position of exon 1 has been shown to produce a similar reduction in N -glycosylation sites on the mu-opioid receptor protein (Huang et al., 2012). Another method for uncovering the functional role of the A118G polymorphism is to replace the mouse DNA sequence of exon 1 of OPRM1 with the human DNA sequence of exon 1, which creates a chimera protein of the mu-opioid (Mahmoud et al., 2011; Freet et al., 2015). Nonetheless, binge-like eating or feeding responses have not been studied in the “humanized” A118G mouse models, and it is unknown whether there are differences in the humanized A118G mouse model.…”