TRPV1 and TRPA1 mediate peripheral nitric oxide-induced nociception in mice.
TRPV1 and TRPA1 mediate peripheral nitric oxide-induced nociception in mice.
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DOI：
10.1371/journal.pone.0007596
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发表时间：
2009-10-29
期刊：
影响因子：
3.7
通讯作者：
Patapoutian A
中科院分区：
文献类型：
--
作者：
Miyamoto T;Dubin AE;Petrus MJ;Patapoutian A
一氧化氮(NO)可引起人的急性疼痛，在炎症和损伤引起的动物模型疼痛敏感化中起重要作用。有证据表明，NO既通过循环GMP途径在中枢神经系统起作用，又在外周通过未知机制作用于感觉神经元。最近有研究表明，在异种系统中，感受伤害性刺激的两个多峰离子通道TRPV1和TRPA1被NO激活。在这里，我们调查这种激活的相关性。我们证明，在分离的内向外贴片记录中，没有供体直接激活TRPV1和TRPA1。培养的初级感觉神经元对NO供体同时表现出TRPV1和TRPA1依赖的反应。BH4是一种产生NO的重要辅助因子，通过钙离子成像检测，它能引起DRG神经元亚群的激活，这种激活至少部分依赖于一氧化氮合酶的活性。我们发现，在TRPA1/TRPV1双基因敲除小鼠的DRG神经元中，BH4诱导的钙内流被消融，这表明内源性水平的NO的产生可以激活这些离子通道。在行为学分析中，当TRPV1和TRPA1都被消融时，外周NO诱导的伤害性感受受到影响。这些结果为NO的外周伤害性作用是由TRPV1和TRPA1共同介导的提供了遗传学证据。
Nitric oxide (NO) can induce acute pain in humans and plays an important role in pain sensitization caused by inflammation and injury in animal models. There is evidence that NO acts both in the central nervous system via a cyclic GMP pathway and in the periphery on sensory neurons through unknown mechanisms. It has recently been suggested that TRPV1 and TRPA1, two polymodal ion channels that sense noxious stimuli impinging on peripheral nociceptors, are activated by NO in heterologous systems. Here, we investigate the relevance of this activation. We demonstrate that NO donors directly activate TRPV1 and TRPA1 in isolated inside-out patch recordings. Cultured primary sensory neurons display both TRPV1- and TRPA1-dependent responses to NO donors. BH4, an essential co-factor for NO production, causes activation of a subset of DRG neurons as assayed by calcium imaging, and this activation is at least partly dependent on nitric oxide synthase activity. We show that BH4-induced calcium influx is ablated in DRG neurons from TRPA1/TRPV1 double knockout mice, suggesting that production of endogenous levels of NO can activate these ion channels. In behavioral assays, peripheral NO-induced nociception is compromised when TRPV1 and TRPA1 are both ablated. These results provide genetic evidence that the peripheral nociceptive action of NO is mediated by both TRPV1 and TRPA1.
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发表时间：
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通讯作者：
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