A Novel Delta Opioid Receptor Antagonist, SoRI-9409, Produces a Selective and Long-Lasting Decrease in Ethanol Consumption in Heavy-Drinking Rats

Abstract

Background Naltrexone, a compound with high affinity for the μ opioid receptor (MOP-R) reduces alcohol consumption. SoRI-9409 is a derivative of naltrexone that has highest affinity at δ opioid receptors (DOP-Rs). We have investigated the effects of SoRI-9409 on ethanol consumption 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, 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 with 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 threefold more effective and selective at reducing ethanol consumption when compared with 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 with 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 might be promising candidates for development as a novel therapeutic for the treatment of alcoholism.

Social and environmental enrichment has different effects on ethanol and sucrose consumption in mice

“…The most commonly reported concentrations are 5 and 10% sucrose. We chose 5% over 10% based on Srisontiyakul's study, to allow comparisons with our previous publications showing that long-term consumption of 5% sucrose using the IA2BC model alters nucleus accumbens morphology and our studies showing the 5% concentration can be used to test novel compounds for their ability to reduce bingelike sucrose consumption (Steensland et al, 2010;Patkar et al, 2017;Nielsen et al, 2008;Shariff et al, 2016;Simms, Haass-Koffler, BitoOnon, Li, & Bartlett, 2012;Simms et al, 2011;Srinivasan et al, 2012).…”

The Role of Delta Opioid Receptors in Ethanol Consumption and Seeking: Implications for New Treatments for Alcohol Use Disorders

“…Naltrexone has been shown to effectively reduce ethanol consumption and seeking in a large number of studies (Ciccocioppo et al, 2002a;Critcher et al, 1983;Franck et al, 1998;Gardell et al, 1996;Le et al, 1999;Nielsen et al, 2008;Simms et al, 2008;Stromberg et al, 1998a;Walker & Koob, 2008). Furthermore, intramuscular injections of naltrexone reduce intravenous (i.v.)…”

“…or oral self-administration of ethanol in rhesus monkeys (Altshuler et al, 1980;Williams et al, 2001). Naltrexone reduces ethanol consumption in both low ethanol consuming rats (Stromberg et al, 1998a) and high ethanol consuming rats (Nielsen et al, 2008;Simms et al, 2008). However, the effects of naltrexone on ethanol consumption are non-selective as fat, sucrose and water intake are also reduced (Corwin & Wojnicki, 2009;Nielsen et al, 2008;Rao et al, 2008;Simms et al, 2008;Wong et al, 2009).…”

“…Naltrexone reduces ethanol consumption in both low ethanol consuming rats (Stromberg et al, 1998a) and high ethanol consuming rats (Nielsen et al, 2008;Simms et al, 2008). However, the effects of naltrexone on ethanol consumption are non-selective as fat, sucrose and water intake are also reduced (Corwin & Wojnicki, 2009;Nielsen et al, 2008;Rao et al, 2008;Simms et al, 2008;Wong et al, 2009). Also, naltrexone reduces alcohol-and cueinduced reinstatement, but not foot-shock stress-induced reinstatement of ethanol-seeking in rodents (Ciccocioppo et al, 2002a;Le et al, 1999;Liu & Weiss, 2002).…”

“…The administration of DOP-R antagonists decreases ethanol consumption and seeking in rats (Franck et al, 1998;Hyytia & Kiianmaa, 2001;June et al, 1999;Krishnan-Sarin et al, 1995b;Marinelli et al, 2009;Nielsen et al, 2011;Nielsen et al, 2008). However, DOP-R antagonists also have been shown to not affect (Ingman et al, 2003;Stromberg et al, 1998a) or increase ethanol intake (Margolis et al, 2008) (Table 1).…”