A Novel Delta Opioid Receptor Antagonist, SoRI-9409, Produces a Selective and Long-Lasting Decrease in Ethanol Consumption in Heavy-Drinking Rats
Received 5 March 2008; received in revised form 12 July 2008; accepted 18 July 2008. published online 09 September 2008.
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.
aErnest Gallo Clinic and Research Center, University of California San Francisco, Emeryville, California
bOrganic Chemistry Department, Southern Research Institute, Birmingham, Alabama
Address reprint requests to Selena E. Bartlett, Ph.D., Ernest Gallo Clinic and Research Center, University of California San Francisco, 5858 Horton Street, Suite 200, Emeryville, CA, 94608
ABSTRACT