14-methoxymetopon, a highly potent μ opioid agonist, biphasically affects ethanol intake in Sardinian alcohol-preferring rats
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Increased opioidergic activity is thought to increase the propensity to consume ethanol. However, the dose monotonicity and receptor subtype for this effect remain uncertain. 14-methoxymetopon is a centrally acting, selective μ opioid receptor agonist with greater systemic antinociceptive potency than morphine and a putatively improved therapeutic index.
To determine whether 14-methoxymetopon influenced voluntary ethanol intake in Sardinian alcohol-preferring (sP) rats.
Male sP rats with continuous 2-bottle choice access to ethanol (10% v/v) or water were subjects. The effects of systemic 14-methoxymetopon administration (2, 5, 12.25, 30 μg/kg, s.c.) on 4-h ethanol intake were determined. The ability of naltrexone (50 μg/kg, s.c.), an opioid antagonist, to block actions of 14-methoxymetopon (12.25, 30 μg/kg, s.c.) was examined as were the effects of 14-methoxymetopon (12.25 μg/kg, s.c.) on self-administered blood alcohol levels (BALs) and clearance of a passive ethanol bolus (1 g/kg). Finally, the effects of central 14-methoxymetopon administration (0.0003–100 ng, i.c.v.) on 4-h ethanol intake were evaluated.
Systemic 14-methoxymetopon very potently and dose-dependently suppressed ethanol and food intake for 30 min, followed by a greater, longer-lasting, and behaviorally specific increase in ethanol intake. The increased ethanol intake led to threefold higher BALs, was naltrexone-reversible, and not due to altered ethanol clearance. Intracerebroventricular 14-methoxymetopon administration rapidly altered ethanol intake per an inverted U-shaped dose-response function, increasing it at a 10 pg dose, while suppressing it at a 10,000-fold higher dose.
The novel μ analgesic increases ethanol intake, a potential therapeutic liability, and results suggest a non-monotonic influence of brain μ opioid receptor stimulation on ethanol intake.
KeywordsHS-198 μ opioid receptor antagonist Morphine Naltrexone Alcohol Preferring Opiate
This is manuscript number 18287 from The Scripps Research Institute. The authors gratefully recognize the editorial assistance of Mike Arends. This work was supported by NIH grants 5P60AA006420 and K99AA016731.
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