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
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
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DOI：
10.1124/jpet.116.238329
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发表时间：
2017-04-01
影响因子：
3.5
通讯作者：
Henderson, Graeme
中科院分区：
文献类型：
--
作者：
Withey, Sarah L.;Hill, Rob;Henderson, Graeme
呼吸抑制是阿片类药物过量死亡的主要原因。我们先前已经表明，用吗啡长时间治疗小鼠诱导对药物的致痛作用的深刻耐受性（Hill等人，2016年）。本研究的目的是调查是否耐受阿片类药物诱导的呼吸抑制蛋白激酶C（PKC）和/或c-Jun N-末端激酶（JNK）介导的。我们发现，虽然小鼠治疗长达6天的吗啡产生耐受性，作为衡量减少的反应，以急性挑战剂量的吗啡，脑渗透PKC抑制剂他莫昔芬和calphostin C的管理恢复急性吗啡的能力，产生呼吸抑制吗啡治疗的小鼠。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药物配体的性质，因为这些PKC抑制剂不会逆转美沙酮长期治疗诱导的耐受性，也不会逆转丁丙诺啡长期治疗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的证据。这些结果表明，蛋白激酶C是吗啡耐受的主要机制，阿片类药物对呼吸抑制的耐受机制是配体依赖性的，同时给予具有蛋白激酶C抑制活性的药物和吗啡（以及海洛因，在体内主要代谢为吗啡）可能使个体更容易通过逆转对吗啡作用的耐受而过量死亡。
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 morphineinduced 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.