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

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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.

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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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Authors and Affiliations

  1. Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, 10550 N. Torrey Pines Road, SP30-2400, La Jolla, CA, 92037, USA

    Valentina Sabino, Pietro Cottone & Eric P. Zorrilla

  2. Harold L. Dorris Neurological Research Institute, The Scripps Research Institute, La Jolla, CA, 92037, USA

    Valentina Sabino, Pietro Cottone & Eric P. Zorrilla

  3. Human Physiology and Pharmacology Department, University of Rome La Sapienza, 00185, Rome, Italy

    Pietro Cottone & Luca Steardo

  4. Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innrain 52a, A-6020, Innsbruck, Austria

    Helmut Schmidhammer

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  1. Valentina Sabino
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  2. Pietro Cottone
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  3. Luca Steardo
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  4. Helmut Schmidhammer
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  5. Eric P. Zorrilla
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Corresponding authors

Correspondence to Valentina Sabino or Eric P. Zorrilla.

Additional information

Valentina Sabino and Pietro Cottone contributed equally to this work.

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Sabino, V., Cottone, P., Steardo, L. et al. 14-methoxymetopon, a highly potent μ opioid agonist, biphasically affects ethanol intake in Sardinian alcohol-preferring rats. Psychopharmacology 192, 537–546 (2007). https://doi.org/10.1007/s00213-007-0746-7

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  • DOI: https://doi.org/10.1007/s00213-007-0746-7

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