14-Methoxymetopon, a highly potent mu opioid agonist, biphasically affects ethanol intake in Sardinian alcohol-preferring rats.
BACKGROUND
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.
Sabino
Valentina
V
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, USA. vsabino@scripp.edu
Cottone
Pietro
P
Steardo
Luca
L
Schmidhammer
Helmut
H
Zorrilla
Eric P
EP
D000428:Alcohol Drinking / Q000503:physiopathology* / Q000523:psychology; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D008297:Male; D009022:Morphine Derivatives / Q000008:administration & dosage / Q000009:adverse effects*; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D017450:Receptors, Opioid, mu / Q000819:agonists*; D012054:Reinforcement, Psychology; D012646:Self Administration
D000701:Analgesics, Opioid; D009022:Morphine Derivatives; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; C081949:14-methoxymetopon; D000431:Ethanol; D009271:Naltrexone