A novel delta opioid receptor antagonist, SoRI-9409, produces a selective and long-lasting decrease in ethanol consumption in heavy-drinking rats.
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 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 [(35)S]GTP gamma S 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 [(35)S]GTP gamma S 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.
Nielsen
Carsten K
CK
Ernest Gallo Clinic and Research Center, University of California San Francisco, Emeryville, California 94608, USA.
Simms
Jeffrey A
JA
Pierson
Haley B
HB
Li
Rui
R
Saini
Surendra K
SK
Ananthan
Subramaniam
S
Bartlett
Selena E
SE
D000428:Alcohol Drinking / Q000188:drug therapy* / Q000523:psychology; D000437:Alcoholism / Q000188:drug therapy / Q000503:physiopathology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000648:ultrastructure; D002755:Choice Behavior / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage; D005518:Food Preferences / Q000187:drug effects; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D008297:Male; D009022:Morphine Derivatives / Q000627:therapeutic use*; D009270:Naloxone / Q000627:therapeutic use; D009292:Narcotic Antagonists / Q000627:therapeutic use; D009294:Narcotics / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D013395:Sucrose / Q000008:administration & dosage
D009022:Morphine Derivatives; D009292:Narcotic Antagonists; D009294:Narcotics; D017465:Receptors, Opioid, delta; C425887:SoRI 9409; D009270:Naloxone; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000431:Ethanol; D013395:Sucrose
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