Does PKC activation increase the homologous desensitization of μ opioid receptors?
Does PKC activation increase the homologous desensitization of μ opioid receptors?
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DOI：
10.1111/bph.12712
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发表时间：
2015-01-01
影响因子：
7.3
通讯作者：
Williams, John T.
中科院分区：
文献类型：
--
作者：
Arttamangkul, Seksiri;Birdsong, William;Williams, John T.
背景与目的本研究探讨了已知的PKC激动剂在吗啡诱导的蓝斑神经元脑片上阿片受体(MOP受体)脱敏中的作用。用两种方法来表征脱敏作用，即应用饱和浓度的激动剂引起的超极化的下降(急性脱敏)和洗去饱和浓度的脑啡肽(ME)引起的超极化的下降(持续脱敏)。从表达Flag-MOP受体的转基因小鼠制备的脑片中研究了MOP受体的内化。结果佛波酯(PMA和PDBu)和毒扁豆碱可增加饱和浓度吗啡和ME所致的急性脱敏反应。这些作用对星形孢菌素不敏感。星状孢子素不能阻断毒扁豆碱引起的超极化的减弱。PDBu和毒扁豆碱不影响ME诱导的持续性脱敏作用，佛波醇酯和毒扁豆碱也不影响吗啡和ME诱导的MOP受体转运。在HEK293细胞中测量到的活化的PKC的分布因应用佛波酯的不同而不同。结论和意义这项研究表明，经常用于评估脱敏的两种测量方法有明显的差异。下降的衡量标准与PKC激动剂引起的峰值幅度下降有很好的相关性，这表明其他因素而不是MOP受体的修饰。链接文章本文是关于阿片类药物：功能选择性的新途径的主题部分的一部分。要查看本节中的其他文章，请访问
Background and PurposeThis study examined the role of agents known to activate PKC on morphine-induced desensitization of -opioid receptors (MOP receptors) in brain slices containing locus coeruleus neurons.Experimental ApproachIntracellular recordings were obtained from rat locus coeruleus neurons. Two measurements were used to characterize desensitization, the decline in hyperpolarization induced by application of a saturating concentration of agonist (acute desensitization) and the decrease in hyperpolarization induced by a subsaturating concentration of [Met](5)enkephalin (ME) following washout of the saturating concentration (sustained desensitization). Internalization of MOP receptors was studied in brain slices prepared from transgenic mice expressing Flag-MOP receptors. The subcellular distribution of activated PKC was examined using a novel fluorescent sensor of PKC in HEK293 cells.Key ResultsThe phorbol esters (PMA and PDBu) and muscarine increased acute desensitization induced by a saturating concentration of morphine and ME. These effects were not sensitive to staurosporine. Staurosporine did not block the decline in hyperpolarization induced by muscarine. PDBu and muscarine did not affect sustained desensitization induced by ME nor did phorbol esters or muscarine change the trafficking of MOP receptors induced by morphine or ME. The distribution of activated PKC measured in HEK293 cells differed depending on which phorbol ester was applied.Conclusions and ImplicationsThis study demonstrates a distinct difference in two measurements that are often used to evaluate desensitization. The measure of decline correlated well with the reduction in peak amplitudes caused by PKC activators implicating the modification of other factors rather than MOP receptors.Linked ArticlesThis article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit