title: Effect of Tamoxifen and Brain-Penetrant Protein Kinase C and c-Jun N-Terminal Kinase Inhibitors on Tolerance to Opioid-Induced Respiratory Depression in Mice.
abstract: Respiratory depression is the major cause of death in opioid overdose. We have previously shown that prolonged treatment of mice with morphine induces profound tolerance to the respiratory-depressant effects of the drug (Hill et al., 2016). The aim of the present study was to investigate whether tolerance to opioid-induced respiratory depression is mediated by protein kinase C (PKC) and/or c-Jun N-terminal kinase (JNK). We found that although mice treated for up to 6 days with morphine developed tolerance, as measured by the reduced responsiveness to an acute challenge dose of morphine, administration of the brain-penetrant PKC inhibitors tamoxifen and calphostin C restored the ability of acute morphine to produce respiratory depression in morphine-treated mice. Importantly, reversal of opioid tolerance was dependent on the nature of the opioid ligand used to induce tolerance, as these PKC inhibitors did not reverse tolerance induced by prolonged treatment of mice with methadone nor did they reverse the protection to acute morphine-induced respiratory depression afforded by prolonged treatment with buprenorphine. We found no evidence for the involvement of JNK in morphine-induced tolerance to respiratory depression. These results indicate that PKC represents a major mechanism underlying morphine tolerance, that the mechanism of opioid tolerance to respiratory depression is ligand-dependent, and that coadministration of drugs with PKC-inhibitory activity and morphine (as well as heroin, largely metabolized to morphine in the body) may render individuals more susceptible to overdose death by reversing tolerance to the effects of morphine.
authors.affiliation: School of Physiology, Pharmacology, and Neuroscience, University of Bristol, Bristol, United Kingdom (S.L.W., R.H., A.L., E.K., G.H.); and Virginia Commonwealth University, Richmond, Virginia (W.L.D.).
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Withey
authors.affiliation: School of Physiology, Pharmacology, and Neuroscience, University of Bristol, Bristol, United Kingdom (S.L.W., R.H., A.L., E.K., G.H.); and Virginia Commonwealth University, Richmond, Virginia (W.L.D.).
authors.forename: Rob
authors.initials: R
authors.lastname: Hill
authors.affiliation: School of Physiology, Pharmacology, and Neuroscience, University of Bristol, Bristol, United Kingdom (S.L.W., R.H., A.L., E.K., G.H.); and Virginia Commonwealth University, Richmond, Virginia (W.L.D.).
authors.forename: Abigail
authors.initials: A
authors.lastname: Lyndon
authors.affiliation: School of Physiology, Pharmacology, and Neuroscience, University of Bristol, Bristol, United Kingdom (S.L.W., R.H., A.L., E.K., G.H.); and Virginia Commonwealth University, Richmond, Virginia (W.L.D.).
authors.forename: William L
authors.initials: WL
authors.lastname: Dewey
authors.affiliation: School of Physiology, Pharmacology, and Neuroscience, University of Bristol, Bristol, United Kingdom (S.L.W., R.H., A.L., E.K., G.H.); and Virginia Commonwealth University, Richmond, Virginia (W.L.D.).
authors.forename: Eamonn
authors.initials: E
authors.lastname: Kelly
authors.affiliation: School of Physiology, Pharmacology, and Neuroscience, University of Bristol, Bristol, United Kingdom (S.L.W., R.H., A.L., E.K., G.H.); and Virginia Commonwealth University, Richmond, Virginia (W.L.D.) Graeme.henderson@bris.ac.uk.
authors.forename: Graeme
authors.initials: G
authors.lastname: Henderson
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004361:Drug Tolerance / Q000502:physiology; D015918:Infusion Pumps, Implantable; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011897:Random Allocation; D012131:Respiratory Insufficiency / Q000139:chemically induced / Q000201:enzymology*; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000701:Analgesics, Opioid; D047428:Protein Kinase Inhibitors; D013629:Tamoxifen; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases