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.
Key Words
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Article info
Publication history
Published online: September 09, 2008
Accepted:
July 18,
2008
Received in revised form:
July 12,
2008
Received:
March 5,
2008
Identification
Copyright
© 2008 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
