Selective blockade of TRPA1 channel attenuates pathological pain without altering noxious cold sensation or body temperature regulation
Selective blockade of TRPA1 channel attenuates pathological pain without altering noxious cold sensation or body temperature regulation
复制标题
DOI：
10.1016/j.pain.2011.01.049
复制
发表时间：
2011-05-01
期刊：
影响因子：
7.4
通讯作者：
Kym, Philip R.
中科院分区：
文献类型：
--
作者：
Chen, Jun;Joshi, Shailen K.;Kym, Philip R.
尽管TRPA 1通道作为疼痛靶点的兴趣越来越大，但其在冷感觉和体温调节中的作用尚不清楚;通道阻断的疗效和特别是副作用仍然知之甚少。在这里，我们使用一种有效的，选择性的和生物可利用的拮抗剂来解决这些问题。A-967079可强效阻断人（IC 50：51 nmol/ L，电生理学，67 nmol/ L，Ca 2+试验）和大鼠TRPA 1（IC 50：101 nmol/ L，电生理学，289 nmol/L，Ca 2+试验）。它对其他TRP通道的选择性> 1000倍，对75种其他离子通道、酶和G蛋白偶联受体的选择性> 150倍。A-967079经口给药在啮齿类动物中产生稳健的药物暴露，并在大鼠中异硫氰酸烯丙酯诱导的疼痛反应和骨关节炎疼痛中表现出镇痛疗效（ED 50：23.2 mg/kg，p.o.）。A-967079减弱神经损伤产生的冷异常性疼痛，但不改变幼稚动物的有害冷感觉，表明TRPA 1在生理和病理状态中的不同作用。与TRPV 1拮抗剂不同，A-967079不会改变体温。它也不会产生运动或心血管副作用。总的来说，这些数据为TRPA 1功能提供了新的见解，并表明选择性TRPA 1阻断可能是缓解疼痛而无不良副作用的可行策略。(C)2011年国际疼痛研究协会。Elsevier B. V.出版，保留所有权利。
Despite the increasing interest in TRPA1 channel as a pain target, its role in cold sensation and body temperature regulation is not clear; the efficacy and particularly side effects resulting from channel blockade remain poorly understood. Here we use a potent, selective, and bioavailable antagonist to address these issues. A-967079 potently blocks human (IC50: 51 nmol/ L, electrophysiology, 67 nmol/ L, Ca2+ assay) and rat TRPA1 (IC50: 101 nmol/ L, electrophysiology, 289 nmol/L, Ca2+ assay). It is > 1000-fold selective over other TRP channels, and is > 150-fold selective over 75 other ion channels, enzymes, and G-protein-coupled receptors. Oral dosing of A-967079 produces robust drug exposure in rodents, and exhibits analgesic efficacy in allyl isothiocyanate-induced nocifensive response and osteoarthritic pain in rats (ED50: 23.2 mg/kg, p.o.). A-967079 attenuates cold allodynia produced by nerve injury but does not alter noxious cold sensation in naive animals, suggesting distinct roles of TRPA1 in physiological and pathological states. Unlike TRPV1 antagonists, A-967079 does not alter body temperature. It also does not produce locomotor or cardiovascular side effects. Collectively, these data provide novel insights into TRPA1 function and suggest that the selective TRPA1 blockade may present a viable strategy for alleviating pain without untoward side effects. (C) 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.