Background: Naltrexone, a compound with high affinity for the mu opioid receptor (MOP-R) reduces alcohol consumption. SoRI-9409 is a derivative of naltrexone that has highest affinity at delta opioid receptors (DOP-Rs). We have investigated the effects of SoRI-9409 on ethanol consumption in order to determine the consequences of altering the naltrexone compound to a form with increased efficacy at DOP-Rs.

Methods: Effects of the opioid receptor antagonists, SoRI-9409 (0-30 mg/kg, intraperitoneal, IP), naltrexone (0-30 mg/kg, IP) or naltrindole (0-10 mg/kg, IP) on ethanol consumption was measured in high and low ethanol consuming rats using two different drinking paradigms. SoRI-9409, naltrexone and naltrindole mediated inhibition of DOP-R stimulated [35S]GTPγS binding was measured in brain membranes prepared from high ethanol consuming rats. The effects of SoRI-9409 on morphine-mediated analgesia, conditioned place preference and anxiety were also examined.

Results: In high but not low ethanol-consuming animals SoRI-9409 is 3-fold more effective and selective at reducing ethanol consumption when compared to naltrexone or naltrindole for up to 24 hours. SoRI-9409 administered daily for 28 days continuously reduced ethanol consumption and when the administration of SoRI-9409 was terminated, the amount of ethanol consumed remained lower compared to vehicle-treated animals. Furthermore, SoRI-9409 inhibits DOP-R stimulated [35S]GTPγS binding in brain membranes of high ethanol consuming rats.

Conclusions: SoRI-9409 causes selective and long-lasting reductions of ethanol consumption. This suggests that compounds that have high affinity for DOP-Rs such as SoRI-9409 may be promising candidates for development as a novel therapeutic for the treatment of alcoholism.