Mode-selective inhibitory effects of eugenol on the mouse TRPV1 channel
Mode-selective inhibitory effects of eugenol on the mouse TRPV1 channel
复制标题
丁子香酚对小鼠 TRPV1 通道的模式选择性抑制作用
DOI：
10.1016/j.bbrc.2021.03.126
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
M. Wakamori
中科院分区：
文献类型：
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作者：
K. Takahashi;T. Yoshida;M. Wakamori
瞬时受体电位香草蛋白1 （TRPV1）通道是感觉神经中的一个多模态受体，参与疼痛感觉。TRPV1至少有三种不同的激活模式，可以被辣椒素、毒热和质子等不同的刺激选择性诱导。尽管许多模式选择性TRPV1拮抗剂因其预期的镇痛作用而被开发出来，但由于烧伤和高温引起的不良反应，很少有成功的报道。丁香酚是一种香草素，在牙科治疗中被用作止痛剂，其TRPV1激活能力已被报道。然而，我们对丁香酚对三种不同模式诱导的TRPV1激活的拮抗作用的潜在机制知之甚少。在这里，我们发现丁香酚剂量依赖性地抑制了辣椒素激活的小鼠TRPV1在人胚胎肾293 （HEK293）细胞中表达的内向电流。在低pH条件下，低浓度的丁香酚只增强了质子诱导的TRPV1电流，而高浓度的丁香酚最初增强了TRPV1电流，但随后立即消除了TRPV1电流。最后，在电生理和基于fura -2的Ca2+成像实验中，丁香酚对热激活的TRPV1没有调节作用。我们的研究结果表明丁香酚是一种模式选择性TRPV1拮抗剂，可以作为靶向TRPV1的镇痛药的先导化合物而没有严重的副作用。
The transient receptor potential vanilloid 1 (TRPV1) channel is a polymodal receptor in sensory nerves and involved in pain sensation. TRPV1 has at least three distinct activation modes that are selectively induced by different stimuli capsaicin, noxious heat, and protons. Although many mode-selective TRPV1 antagonists have been developed for their anticipated analgesic effects, there have been few successful reports because of adverse effects due to burn injuries and hyperthermia.Eugenol is a vanilloid that has been used as an analgesic in the dental treatment, and its TRPV1 activation ability has been reported. However, our knowledge about the underlying mechanisms of the antagonistic effects of eugenol on TRPV1 activation induced by three different modes is limited.Here, we show that eugenol dose-dependently inhibited the capsaicin-activated inward currents of mouse TRPV1 expressed in human embryonic kidney 293 (HEK293) cells. Under low pH conditions, low concentrations of eugenol only enhanced the proton-induced TRPV1 currents, whereas high eugenol concentrations initially potentiated but then immediately abrogated TRPV1 currents. Finally, eugenol had no modulatory effects on heat-activated TRPV1 in electrophysiological and Fura-2-based Ca2+imaging experiments.Our results demonstrate that eugenol is a mode-selective antagonist of TRPV1 and can be evaluated as a lead compound of analgesics targeting TRPV1 without serious side effects.