Transient receptor potential channels in sensory neurons are targets of the antimycotic agent clotrimazole
Transient receptor potential channels in sensory neurons are targets of the antimycotic agent clotrimazole
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DOI：
10.1523/jneurosci.4772-07.2008
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发表时间：
2008-01-16
影响因子：
5.3
通讯作者：
Voets, Thomas
中科院分区：
文献类型：
--
作者：
Meseguer, Victor;Karashima, Yuji;Voets, Thomas
克霉唑（CLT）是一种广泛使用的局部治疗皮肤、阴道和口腔酵母菌感染的药物。局部CLT应用的常见副作用包括皮肤和粘膜的刺激和烧灼痛。在这里，我们提供的证据表明，瞬时受体电位（TRP）通道在初级感觉神经元的基础这些不必要的影响CLT。我们发现，临床相关的CLT浓度激活异源表达的TRPV 1和TRPA 1，两个TRP通道，作为刺激性化学和/或热刺激的受体在伤害性神经元。与此一致，CLT刺激了辣椒素敏感和芥子油敏感的三叉神经元的子集，并通过足底注射诱发小鼠的伤害性行为和热超敏反应。值得注意的是，CLT诱导的疼痛行为被TRPV 1拮抗剂BCTC [（N-（-4-叔丁基苯基）-4-（3-氯吡啶-2-基）四氢吡嗪-1（2 H）-甲酰胺）]抑制，并且在TRPV 1缺陷小鼠中不存在。此外，CLT抑制冷和薄荷醇受体TRPM 8，并阻断辣椒素和芥子油不敏感的三叉神经元薄荷醇诱导的反应。内向TRPM 8电流的50%抑制浓度（IC 50）与200 nM相似，使CLT成为已知最有效的TRPM 8拮抗剂，也是区分TRPM 8和TRPA 1介导的反应的有用工具。总之，我们的研究结果确定TRP通道的感觉神经元作为分子靶点的CLT，并提供手段，以开发新的CLT制剂，减少不必要的感觉副作用。
Clotrimazole (CLT) is a widely used drug for the topical treatment of yeast infections of skin, vagina, and mouth. Common side effects of topical CLT application include irritation and burning pain of the skin and mucous membranes. Here, we provide evidence that transient receptor potential (TRP) channels in primary sensory neurons underlie these unwanted effects of CLT. We found that clinically relevant CLT concentrations activate heterologously expressed TRPV1 and TRPA1, two TRP channels that act as receptors of irritant chemical and/or thermal stimuli in nociceptive neurons. In line herewith, CLT stimulated a subset of capsaicin-sensitive and mustard oil-sensitive trigeminal neurons, and evoked nocifensive behavior and thermal hypersensitivity with intraplantar injection in mice. Notably, CLT-induced pain behavior was suppressed by the TRPV1-antagonist BCTC [(N-(-4-tertiarybutylphenyl)-4-(3-cholorpyridin-2-yl) tetrahydropyrazine-1(2H)-carboxamide)] and absent in TRPV1-deficient mice. In addition, CLT inhibited the cold and menthol receptor TRPM8, and blocked menthol-induced responses in capsaicin-and mustard oil-insensitive trigeminal neurons. The concentration for 50% inhibition (IC50) of inward TRPM8 current was similar to 200 nM, making CLT the most potent known TRPM8 antagonist and a useful tool to discriminate between TRPM8- and TRPA1-mediated responses. Together, our results identify TRP channels in sensory neurons as molecular targets of CLT, and offer means to develop novel CLT preparations with fewer unwanted sensory side effects.