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Psychopharmacology

, Volume 192, Issue 4, pp 537–546 | Cite as

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

  • Valentina SabinoEmail author
  • Pietro Cottone
  • Luca Steardo
  • Helmut Schmidhammer
  • Eric P. ZorrillaEmail author
Original Investigation

Abstract

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 μ 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 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.

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 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.

Keywords

HS-198 μ opioid receptor antagonist Morphine Naltrexone Alcohol Preferring Opiate 

Notes

Acknowledgement

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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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  1. 1.Committee on the Neurobiology of Addictive DisordersThe Scripps Research InstituteLa JollaUSA
  2. 2.Harold L. Dorris Neurological Research InstituteThe Scripps Research InstituteLa JollaUSA
  3. 3.Human Physiology and Pharmacology DepartmentUniversity of Rome La SapienzaRomeItaly
  4. 4.Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences InnsbruckUniversity of InnsbruckInnsbruckAustria

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