PT  - JOURNAL ARTICLE
AU  - Javier Llorente
AU  - Sarah Withey
AU  - Guadalupe Rivero
AU  - Margaret Cunningham
AU  - Alex Cooke
AU  - Kunal Saxena
AU  - Jamie McPherson
AU  - Sue Oldfield
AU  - William L. Dewey
AU  - Chris P. Bailey
AU  - Eamonn Kelly
AU  - Graeme Henderson
TI  - Ethanol Reversal of Cellular Tolerance to Morphine in Rat Locus Coeruleus Neurons
AID  - 10.1124/mol.113.085936
DP  - 2013 Aug 01
TA  - Molecular Pharmacology
PG  - 252--260
VI  - 84
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/84/2/252.short
4100  - http://molpharm.aspetjournals.org/content/84/2/252.full
SO  - Mol Pharmacol2013 Aug 01; 84
AB  - 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.