Systemic desensitization through TRPA1 channels by capsazepine and mustard oil - a novel strategy against inflammation and pain.
Systemic desensitization through TRPA1 channels by capsazepine and mustard oil - a novel strategy against inflammation and pain.
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DOI：
10.1038/srep28621
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发表时间：
2016-06-30
影响因子：
4.6
通讯作者：
Engel MA
中科院分区：
文献类型：
--
作者：
Kistner K;Siklosi N;Babes A;Khalil M;Selescu T;Zimmermann K;Wirtz S;Becker C;Neurath MF;Reeh PW;Engel MA
我们证明了一种新的双重策略，通过全身脱敏的伤害感受器通过TRPA 1炎症和疼痛。辣椒平（CPZ）对实验性结肠炎的减轻作用长期以来一直归因于其对TRPV 1的拮抗作用和对神经源性炎症的相关抑制。相反，我们发现CPZ通过TRPA 1的深度脱敏发挥其抗炎作用。微摩尔浓度的CPZ诱导野生型（WT）而非TRPA 1缺陷小鼠的背根神经节（DRG）神经元中的钙内流。CPZ诱导的人TRPA 1表达HEK 293 t细胞中的钙瞬变被选择性TRPA 1拮抗剂HC 030031和A967079阻断，并涉及N-末端结构域中的三个半胱氨酸残基。有趣的是，结肠灌肠和饮用含有CPZ的水都会导致WT和TRPV 1 −/−小鼠的严重全身性痛觉减退，但TRPA 1 −/−小鼠则不会。这些发现可能会指导一类新的具有抗炎和抗伤害作用的疾病修饰药物的开发。
We demonstrate a novel dual strategy against inflammation and pain through body-wide desensitization of nociceptors via TRPA1. Attenuation of experimental colitis by capsazepine (CPZ) has long been attributed to its antagonistic action on TRPV1 and associated inhibition of neurogenic inflammation. In contrast, we found that CPZ exerts its anti-inflammatory effects via profound desensitization of TRPA1. Micromolar CPZ induced calcium influx in isolated dorsal root ganglion (DRG) neurons from wild-type (WT) but not TRPA1-deficient mice. CPZ-induced calcium transients in human TRPA1-expressing HEK293t cells were blocked by the selective TRPA1 antagonists HC 030031 and A967079 and involved three cysteine residues in the N-terminal domain. Intriguingly, both colonic enemas and drinking water with CPZ led to profound systemic hypoalgesia in WT and TRPV1−/− but not TRPA1−/− mice. These findings may guide the development of a novel class of disease-modifying drugs with anti-inflammatory and anti-nociceptive effects.