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Research ArticleArticle

Ethanol Reversal of Cellular Tolerance to Morphine in Rat Locus Coeruleus Neurons

Javier Llorente, Sarah Withey, Guadalupe Rivero, Margaret Cunningham, Alex Cooke, Kunal Saxena, Jamie McPherson, Sue Oldfield, William L. Dewey, Chris P. Bailey, Eamonn Kelly and Graeme Henderson
Molecular Pharmacology August 2013, 84 (2) 252-260; DOI: https://doi.org/10.1124/mol.113.085936
Javier Llorente
School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (J.L., S.W., G.R., M.C., A.C., K.S., J.M., S.O., E.K., G.H.); Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (W.L.D.); and Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (C.P.B.)
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Sarah Withey
School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (J.L., S.W., G.R., M.C., A.C., K.S., J.M., S.O., E.K., G.H.); Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (W.L.D.); and Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (C.P.B.)
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Guadalupe Rivero
School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (J.L., S.W., G.R., M.C., A.C., K.S., J.M., S.O., E.K., G.H.); Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (W.L.D.); and Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (C.P.B.)
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Margaret Cunningham
School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (J.L., S.W., G.R., M.C., A.C., K.S., J.M., S.O., E.K., G.H.); Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (W.L.D.); and Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (C.P.B.)
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Alex Cooke
School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (J.L., S.W., G.R., M.C., A.C., K.S., J.M., S.O., E.K., G.H.); Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (W.L.D.); and Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (C.P.B.)
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Kunal Saxena
School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (J.L., S.W., G.R., M.C., A.C., K.S., J.M., S.O., E.K., G.H.); Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (W.L.D.); and Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (C.P.B.)
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Jamie McPherson
School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (J.L., S.W., G.R., M.C., A.C., K.S., J.M., S.O., E.K., G.H.); Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (W.L.D.); and Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (C.P.B.)
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Sue Oldfield
School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (J.L., S.W., G.R., M.C., A.C., K.S., J.M., S.O., E.K., G.H.); Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (W.L.D.); and Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (C.P.B.)
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William L. Dewey
School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (J.L., S.W., G.R., M.C., A.C., K.S., J.M., S.O., E.K., G.H.); Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (W.L.D.); and Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (C.P.B.)
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Chris P. Bailey
School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (J.L., S.W., G.R., M.C., A.C., K.S., J.M., S.O., E.K., G.H.); Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (W.L.D.); and Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (C.P.B.)
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Eamonn Kelly
School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (J.L., S.W., G.R., M.C., A.C., K.S., J.M., S.O., E.K., G.H.); Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (W.L.D.); and Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (C.P.B.)
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Graeme Henderson
School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (J.L., S.W., G.R., M.C., A.C., K.S., J.M., S.O., E.K., G.H.); Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (W.L.D.); and Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (C.P.B.)
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Abstract

Consumption of ethanol is a considerable risk factor for death in heroin overdose. We sought to determine whether a mildly intoxicating concentration of ethanol could alter morphine tolerance at the cellular level. In rat locus coeruleus (LC) neurons, tolerance to morphine was reversed by acute exposure of the brain slice to ethanol (20 mM). Tolerance to the opioid peptide [d-Ala2,N-MePhe4,Gly-ol]-enkephalin was not reversed by ethanol. Previous studies in LC neurons have revealed a role for protein kinase C (PKC)α in μ-opioid receptor (MOPr) desensitization by morphine and in the induction and maintenance of morphine tolerance, but we have been unable to demonstrate that 20 mM ethanol produces significant inhibition of PKCα. The ability of ethanol to reverse cellular tolerance to morphine in LC neurons was absent in the presence of the phosphatase inhibitor okadaic acid, indicating that dephosphorylation is involved. In human embryonic kidney 293 cells expressing the MOPr, ethanol reduced the level of MOPr phosphorylation induced by morphine. Ethanol reversal of tolerance did not appear to result from a direct effect on MOPr since acute exposure to ethanol (20 mM) did not modify the affinity of binding of morphine to the MOPr or the efficacy of morphine for G-protein activation as measured by guanosine 5′-O-(3-[35S]thio)triphosphate binding. Similarly, ethanol did not affect MOPr trafficking. We conclude that acute exposure to ethanol enhances the effects of morphine by reversing the processes underlying morphine cellular tolerance.

Footnotes

    • Received March 1, 2013.
    • Accepted May 28, 2013.
  • This work was funded by the National Institutes of Health National Institute on Drug Abuse [International Collaboration Grant DA 020836].

  • dx.doi.org/10.1124/mol.113.085936.

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

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 84 (2)
Molecular Pharmacology
Vol. 84, Issue 2
1 Aug 2013
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Research ArticleArticle

Ethanol Reversal of Morphine Tolerance

Javier Llorente, Sarah Withey, Guadalupe Rivero, Margaret Cunningham, Alex Cooke, Kunal Saxena, Jamie McPherson, Sue Oldfield, William L. Dewey, Chris P. Bailey, Eamonn Kelly and Graeme Henderson
Molecular Pharmacology August 1, 2013, 84 (2) 252-260; DOI: https://doi.org/10.1124/mol.113.085936

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Research ArticleArticle

Ethanol Reversal of Morphine Tolerance

Javier Llorente, Sarah Withey, Guadalupe Rivero, Margaret Cunningham, Alex Cooke, Kunal Saxena, Jamie McPherson, Sue Oldfield, William L. Dewey, Chris P. Bailey, Eamonn Kelly and Graeme Henderson
Molecular Pharmacology August 1, 2013, 84 (2) 252-260; DOI: https://doi.org/10.1124/mol.113.085936
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