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 micro 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 micro/kg, s.c.) on 4-h ethanol intake were determined. The ability of naltrexone (50 micro/kg, s.c.), an opioid antagonist, to block actions of 14-methoxymetopon (12.25, 30 micro/kg, s.c.) was examined as were the effects of 14-methoxymetopon (12.25 micro/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. 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 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. 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.
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 micro 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 micro/kg, s.c.) on 4-h ethanol intake were determined. The ability of naltrexone (50 micro/kg, s.c.), an opioid antagonist, to block actions of 14-methoxymetopon (12.25, 30 micro/kg, s.c.) was examined as were the effects of 14-methoxymetopon (12.25 micro/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. 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 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. 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.
Authors: George F Koob; Amanda J Roberts; Brigitte L Kieffer; Charles J Heyser; Simon N Katner; Roberto Ciccocioppo; Friedbert Weiss Journal: Recent Dev Alcohol Date: 2003
Authors: Valentina Sabino; Pietro Cottone; Angelo Blasio; Malliga R Iyer; Luca Steardo; Kenner C Rice; Bruno Conti; George F Koob; Eric P Zorrilla Journal: Neuropsychopharmacology Date: 2011-02-23 Impact factor: 7.853
Authors: Attilio Iemolo; Angelo Blasio; Stephen A St Cyr; Fanny Jiang; Kenner C Rice; Valentina Sabino; Pietro Cottone Journal: Neuropsychopharmacology Date: 2013-06-10 Impact factor: 7.853
Authors: Richard L Bell; Helen J K Sable; Giancarlo Colombo; Petri Hyytia; Zachary A Rodd; Lawrence Lumeng Journal: Pharmacol Biochem Behav Date: 2012-07-25 Impact factor: 3.533