Ethanol reversal of cellular tolerance to morphine in rat locus coeruleus neurons

J. Llorente, S. Withey, G. Rivero, M. Cunningham, A. Cooke, K. Saxena, J. McPherson, S. Oldfield, W.L. Dewey, C.P. Bailey, E. Kelly, G. Henderson

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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-Ala ,N-MePhe,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 asmeasured by guanosine 5′-O-(3-[S]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.
Original languageEnglish
Pages (from-to)252-260
Number of pages9
JournalMolecular Pharmacology
Volume84
Issue number2
Early online date28 May 2013
DOIs
Publication statusPublished - Aug 2013

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Locus Coeruleus
Morphine
Ethanol
Neurons
Guanosine 5'-O-(3-Thiotriphosphate)
Protein Kinase C-alpha
Okadaic Acid
Opioid Peptides
Enkephalins
mu Opioid Receptor
Heroin
GTP-Binding Proteins
Phosphoric Monoester Hydrolases
Maintenance
Phosphorylation
Kidney

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Llorente, J., Withey, S., Rivero, G., Cunningham, M., Cooke, A., Saxena, K., ... Henderson, G. (2013). Ethanol reversal of cellular tolerance to morphine in rat locus coeruleus neurons. Molecular Pharmacology, 84(2), 252-260. https://doi.org/10.1124/mol.113.085936

Ethanol reversal of cellular tolerance to morphine in rat locus coeruleus neurons. / Llorente, J.; Withey, S.; Rivero, G.; Cunningham, M.; Cooke, A.; Saxena, K.; McPherson, J.; Oldfield, S.; Dewey, W.L.; Bailey, C.P.; Kelly, E.; Henderson, G.

In: Molecular Pharmacology, Vol. 84, No. 2, 08.2013, p. 252-260.

Research output: Contribution to journalArticle

Llorente, J, Withey, S, Rivero, G, Cunningham, M, Cooke, A, Saxena, K, McPherson, J, Oldfield, S, Dewey, WL, Bailey, CP, Kelly, E & Henderson, G 2013, 'Ethanol reversal of cellular tolerance to morphine in rat locus coeruleus neurons', Molecular Pharmacology, vol. 84, no. 2, pp. 252-260. https://doi.org/10.1124/mol.113.085936
Llorente J, Withey S, Rivero G, Cunningham M, Cooke A, Saxena K et al. Ethanol reversal of cellular tolerance to morphine in rat locus coeruleus neurons. Molecular Pharmacology. 2013 Aug;84(2):252-260. https://doi.org/10.1124/mol.113.085936
Llorente, J. ; Withey, S. ; Rivero, G. ; Cunningham, M. ; Cooke, A. ; Saxena, K. ; McPherson, J. ; Oldfield, S. ; Dewey, W.L. ; Bailey, C.P. ; Kelly, E. ; Henderson, G. / Ethanol reversal of cellular tolerance to morphine in rat locus coeruleus neurons. In: Molecular Pharmacology. 2013 ; Vol. 84, No. 2. pp. 252-260.
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