14-methoxymetopon, a highly potent μ opioid agonist, biphasically affects ethanol intake in Sardinian alcohol-preferring rats

Rationale 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 mu opioid receptor agonist with greater systemic antinociceptive potency than morphine and a putatively improved therapeutic index. Objective To determine whether 14-methoxymetopon influenced voluntary ethanol intake in Sardinian alcohol-preferring (sP) rats. Methods 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 mu g/ kg, s.c.) on 4-h ethanol intake were determined. The ability of naltrexone (50 mu g/kg, s.c.), an opioid antagonist, to block actions of 14-methoxymetopon (12.25, 30 mu g/ kg, s.c.) was examined as were the effects of 14-methoxymetopon (12.25 mu g/kg, s.c.) on self- administered blood alcohol levels (BALs) and clearance of a passive ethanol bolus (1g/kg). Finally, the effects of central 14-methoxymetopon administration (0.0003-100 ng, i.c.v.) on 4-h ethanol intake were evaluated. Results 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 naltrex-one-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. Conclusions The novel mu analgesic increases ethanol intake, a potential therapeutic liability, and results suggest a non-monotonic influence of brain mu opioid receptor stimulation on ethanol intake.