Withey Sarah L, Hill Rob, Lyndon Abigail, Dewey William L, Kelly Eamonn, Henderson Graeme
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.).
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.)
J Pharmacol Exp Ther. 2017 Apr;361(1):51-59. doi: 10.1124/jpet.116.238329. Epub 2017 Jan 27.
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.
呼吸抑制是阿片类药物过量致死的主要原因。我们之前已经表明，用吗啡长期治疗小鼠会使其对该药物的呼吸抑制作用产生显著耐受性（希尔等人，2016年）。本研究的目的是调查对阿片类药物诱导的呼吸抑制的耐受性是否由蛋白激酶C（PKC）和/或c-Jun氨基末端激酶（JNK）介导。我们发现，尽管用吗啡治疗长达6天的小鼠产生了耐受性，这通过对急性挑战剂量吗啡的反应性降低来衡量，但给予可穿透大脑的PKC抑制剂他莫昔芬和钙泊三醇可恢复急性吗啡在吗啡治疗小鼠中产生呼吸抑制的能力。重要的是，阿片类药物耐受性的逆转取决于用于诱导耐受性的阿片类配体的性质，因为这些PKC抑制剂并不能逆转用美沙酮长期治疗小鼠所诱导的耐受性，也不能逆转用丁丙诺啡长期治疗所提供的对急性吗啡诱导的呼吸抑制的保护作用。我们没有发现JNK参与吗啡诱导的呼吸抑制耐受性的证据。这些结果表明，PKC是吗啡耐受性的主要潜在机制，阿片类药物对呼吸抑制的耐受性机制是配体依赖性的，并且将具有PKC抑制活性的药物与吗啡（以及海洛因，在体内大部分代谢为吗啡）共同给药可能会通过逆转对吗啡作用的耐受性而使个体更容易死于过量用药。
