Leffler Andreas, Fischer Michael J, Rehner Dietlinde, Kienel Stephanie, Kistner Katrin, Sauer Susanne K, Gavva Narender R, Reeh Peter W, Nau Carla
Department of Anesthesiology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
J Clin Invest. 2008 Feb;118(2):763-76. doi: 10.1172/JCI32751.
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.
局部麻醉药（LAs）通过与电压门控性Na(+)通道的特定位点相互作用，阻断动作电位的产生和传导。LAs还可通过尚未明确的机制兴奋感觉神经元并具有神经毒性。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，使这些神经元对多种损伤敏感。在此，我们证明局部麻醉药利多卡因可激活啮齿动物背根神经节感觉神经元以及表达TRPV1或TRPA1的HEK293t细胞中的TRP通道家族受体TRPV1，并在较小程度上激活TRPA1。利多卡因还可诱导降钙素基因相关肽（CGRP）从离体皮肤和外周神经中以TRPV1依赖的方式释放。TRPV1对利多卡因的敏感性需要跨膜结构域3内及相邻的假定香草酸结合结构域片段，在磷脂酰肌醇4,5-二磷酸耗竭时降低，并被TRP结构域近端C末端R701位点的点突变消除。这些数据确定TRPV1和TRPA1是局部麻醉药诱导伤害感受器兴奋的假定关键元件。这种效应足以释放CGRP，即神经源性炎症的关键成分，因此有必要研究TRPV1和TRPA1在局部麻醉药诱导的神经毒性中的作用。
