MRGPRX1 antagonists(Escient Pharmaceuticals)

Alcohol use disorder (AUD) is a major cause of morbidity and mortality worldwide, for which new efficacious treatments are necessary. The opioid receptor system is a mediator of the rewarding effects of alcohol; in particular, while activation of μ opioid receptors enhances ethanol intake in rodents, opioid-receptor antagonists, such as naloxone and naltrexone, reduce its pleasurable and reinforcing effects, thereby decreasing alcohol. Sigma receptors (Sig-Rs) have been proposed as modulators of the effects of alcohol and, therefore, as a potential new pharmacological target for AUD. Somewhat analogously to μ opioid ligands, SigR agonists increase, while SigR antagonists decrease alcohol intake in animal models of excessive alcohol drinking. However, a potential cross-talk between these two receptor systems in relation to alcohol consumption has so far not been investigated. Here, we addressed this question pharmacologically, by testing the effects of either activating or inhibiting opioid receptors on the heavy alcohol drinking induced by chronic stimulation of SigR in alcohol-preferring rats. We found that the opioid receptor agonist morphine, which per se increases ethanol intake, at a sub-threshold dose reduces the binge-like drinking induced by the repeated treatment with the SigR agonist 1,3-di-o-tolylguanidine (DTG); conversely, the opioid receptor antagonist naltrexone, which per se reduces ethanol intake, at a sub-threshold dose potentiates the DTG-induced binge-like drinking. Our data show a cross-talk between the opioid and SigR systems relevant to the modulation of alcohol drinking, which provides important insights into the neurobiology of AUD and may lead to the development of novel therapies, either standalone or in combination.