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Research ArticleNeuropharmacology

Reversal of Morphine Analgesic Tolerance by Ethanol in the Mouse

L. C. Hull, B. H. Gabra, C. P. Bailey, G. Henderson and W. L. Dewey
Journal of Pharmacology and Experimental Therapeutics June 2013, 345 (3) 512-519; DOI: https://doi.org/10.1124/jpet.112.202184
L. C. Hull
Department of Pharmacology and Toxicology, Virginia Commonwealth University Medical Center, Richmond, Virginia (L.C.H., B.H.G., W.L.D.); Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (C.P.B.); and Department of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (G.H.)
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B. H. Gabra
Department of Pharmacology and Toxicology, Virginia Commonwealth University Medical Center, Richmond, Virginia (L.C.H., B.H.G., W.L.D.); Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (C.P.B.); and Department of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (G.H.)
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C. P. Bailey
Department of Pharmacology and Toxicology, Virginia Commonwealth University Medical Center, Richmond, Virginia (L.C.H., B.H.G., W.L.D.); Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (C.P.B.); and Department of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (G.H.)
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G. Henderson
Department of Pharmacology and Toxicology, Virginia Commonwealth University Medical Center, Richmond, Virginia (L.C.H., B.H.G., W.L.D.); Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (C.P.B.); and Department of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (G.H.)
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W. L. Dewey
Department of Pharmacology and Toxicology, Virginia Commonwealth University Medical Center, Richmond, Virginia (L.C.H., B.H.G., W.L.D.); Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (C.P.B.); and Department of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (G.H.)
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Abstract

The chronic use of opioids in humans, accompanied by the development of tolerance, is a dangerous phenomenon in its own right. However, chronic opioid use is often made more dangerous by the coconsumption of other substances. It has been observed that the blood level of opioids in postmortem analyses of addicts, who consumed ethanol along with the opioid, was much less than that observed in individuals who died from opioids alone. This relationship between ethanol and opioids led us to investigate the hypothesis that ethanol alters tolerance to opioids. In the present study, we report that ethanol significantly and dose-dependently reduced the antinociceptive tolerance produced by morphine and the cross-tolerance between [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) and morphine in the mouse tail-flick test. The reversal of morphine tolerance was partially blocked by both the gamma receptor blocker bicuculline and by the γ-aminobutyric acid (GABA)B receptor blocker phaclofen and the administration of both inhibitors completely reversed the effects of ethanol on morphine tolerance. Diazepam, like ethanol, decreased morphine tolerance. However, this inhibition was reversed by the GABAA antagonist bicuculline but not by the GABAB antagonist phaclofen. These findings have important implications for individuals who abuse opioids and ethanol as well as suggest a mechanism to reduce the amount of opioid needed in chronic pain treatment.

Footnotes

    • Received December 6, 2012.
    • Accepted March 21, 2013.
  • This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants DA007027 and DA020836].

  • dx.doi.org/10.1124/jpet.112.202184.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 345 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 345, Issue 3
1 Jun 2013
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Research ArticleNeuropharmacology

Reversal of Morphine Analgesic Tolerance by Ethanol

L. C. Hull, B. H. Gabra, C. P. Bailey, G. Henderson and W. L. Dewey
Journal of Pharmacology and Experimental Therapeutics June 1, 2013, 345 (3) 512-519; DOI: https://doi.org/10.1124/jpet.112.202184

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Research ArticleNeuropharmacology

Reversal of Morphine Analgesic Tolerance by Ethanol

L. C. Hull, B. H. Gabra, C. P. Bailey, G. Henderson and W. L. Dewey
Journal of Pharmacology and Experimental Therapeutics June 1, 2013, 345 (3) 512-519; DOI: https://doi.org/10.1124/jpet.112.202184
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