The vanilloid receptor TRPV1 is activated and sensitized by local anesthetics in rodent sensory neurons
The vanilloid receptor TRPV1 is activated and sensitized by local anesthetics in rodent sensory neurons
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DOI：
10.1172/jci32751
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发表时间：
2008-02-01
影响因子：
15.9
通讯作者：
Nau, Carla
中科院分区：
文献类型：
--
作者：
Leffler, Andreas;Fischer, Michael J.;Nau, Carla
局麻药(LAS)通过与电压门控Na+通道的特定部位相互作用，阻断动作电位的产生和传播。LAS还可以兴奋感觉神经元，并通过尚不清楚的机制产生神经毒性。瞬时受体电位(TRP)通道家族的非特异性阳离子通道主要由伤害性感觉神经元表达，使这些神经元对各种伤害敏感。在此，我们证明了LA利多卡因激活了啮齿动物背根神经节感觉神经元和HEK293t细胞中的TRPV1和TRPA1受体。利多卡因还可诱导皮肤和周围神经释放依赖于TRPV1的降钙素基因相关肽(CGRP)。TRPV1跨膜区3内和邻近的假定香草素结合结构域的片段对利多卡因的敏感性在磷脂酰肌醇4，5-二磷酸缺失时降低，并被近端C-末端Trp结构域R701残基的点突变所消除。这些数据表明，TRPV1和TRPA1可能是LA诱导的伤害性感受器兴奋的关键元件。这种作用足以释放神经源性炎症的关键成分CGRP，并值得研究TRPV1和TRPA1在LA诱导的神经毒性中的作用。
Local anesthetics (LAs) block the generation and propagation of action potentials by interacting with specific sites of voltage-gated Na+ channels. LAs can also excite sensory neurons and be neurotoxic through mechanisms that are as yet undefined. Nonspecific cation channels of the transient receptor potential (TRP) channel family that are predominantly expressed by nociceptive sensory neurons render these neurons sensitive to a variety of insults. Here we demonstrated that the LA lidocaine activated TRP channel family receptors TRPV1 and, to a lesser extent, TRPA1 in rodent dorsal root ganglion sensory neurons as well as in HEK293t cells expressing TRPV1 or TRPA1. Lidocaine also induced a TRPV1-dependent release of calcitonin gene-related peptide (CGRP) from isolated skin and peripheral nerve. Lidocaine sensitivity of TRPV1 required segments of the putative vanilloid-binding domain within and adjacent to transmembrane domain 3, was diminished under phosphatidylinositol 4,5-bisphosphate depletion, and was abrogated by a point mutation at residue R701 in the proximal C-terminal TRP domain. These data identify TRPV1 and TRPA1 as putative key elements of LA-induced nociceptor excitation. This effect is sufficient to release CGRP, a key component of neurogenic inflammation, and warrants investigation into the role of TRPV1 and TRPA1 in LA-induced neurotoxicity.