Sensitization of TRPV1 and TRPA1 via peripheral mGluR5 signaling contributes to thermal and mechanical hypersensitivity
Sensitization of TRPV1 and TRPA1 via peripheral mGluR5 signaling contributes to thermal and mechanical hypersensitivity
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DOI：
10.1097/j.pain.0000000000000973
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发表时间：
2017-09-01
期刊：
影响因子：
7.4
通讯作者：
Iwata, Koichi
中科院分区：
文献类型：
--
作者：
Honda, Kuniya;Shinoda, Masamichi;Iwata, Koichi
周围组织炎症或损伤导致伤害性轴突、角质形成细胞和雪旺细胞释放谷氨酸，导致热超敏反应。然而，谷氨酸引起的热超敏反应的详细分子机制尚不清楚。本研究的目的是阐明外周瞬时受体电位 (TRP)、TRP 香草酸 1 (TRPV1)、TRP 锚蛋白 1 (TRPA1) 和蛋白激酶 C epsilon (PKC epsilon) 在谷氨酸诱导的疼痛超敏反应中的作用。面部注射弗氏完全佐剂后3天，面部组织中谷氨酸含量明显增加。与注射载体的大鼠相比，在面部皮肤连续注射谷氨酸或代谢型谷氨酸受体 5 (mGluR5) 激动剂 (CHPG) 后第 7 天，对热、冷或机械刺激的退头反射阈值显着降低，并且 mGluR5 拮抗剂 MTEP、TRPA1 显着恢复了谷氨酸诱导的超敏反应 将拮抗剂 HC-030031、TRPV1 拮抗剂 SB366791 或 PKC epsilon 易位抑制剂注射到面部皮肤。 TRPV1 和 TRPA1 在支配面部皮肤的 mGluR5 免疫反应性 (IR) 三叉神经节 (TG) 神经元中表达，mGluR5-IR TG 神经元表达 PKC epsilon。与注射媒介物相比，注射谷氨酸、注射盐水和幼稚大鼠中GluR5-IR TG神经元的数量没有显着差异，而在面部皮肤连续注射谷氨酸后7天，TRPV1-或TRPA1-IR TG神经元的数量显着增加。将谷氨酸注射到面部皮肤后，TG 中的 PKC epsilon 磷酸化显着增强。此外，面部谷氨酸治疗后 TG 神经元的神经元活性显着增加。目前的研究结果表明，TRPA1 和/或 TRPV1 通过 PKC epsilon 的 mGluR5 信号传导致敏与面部热和机械超敏反应有关。
Peripheral tissue inflammation or injury causes glutamate release from nociceptive axons, keratinocytes, and Schwann cells, resulting in thermal hypersensitivity. However, the detailed molecular mechanisms underlying glutamate-induced thermal hypersensitivity are unknown. The aim of this study was to clarify the involvement of peripheral transient receptor potential (TRP) TRP vanilloid 1 (TRPV1), TRP ankyrin 1 (TRPA1), and protein kinase C epsilon (PKC epsilon) in glutamate-induced pain hypersensitivity. The amount of glutamate in the facial tissue was significantly increased 3 days after facial Complete Freund's adjuvant injection. The head-withdrawal reflex threshold to heat, cold, or mechanical stimulation was significantly decreased on day 7 after continuous glutamate or metabotropic glutamate receptor 5 (mGluR5) agonist (CHPG) injection into the facial skin compared with vehicle-injected rats, and glutamate-induced hypersensitivity was significantly recovered by mGluR5 antagonist MTEP, TRPA1 antagonist HC-030031, TRPV1 antagonist SB366791, or PKC epsilon translocation inhibitor administration into the facial skin. TRPV1 and TRPA1 were expressed in mGluR5-immunoreactive (IR) trigeminal ganglion (TG) neurons innervating the facial skin, and mGluR5-IR TG neurons expressed PKC epsilon. There was no significant difference in the number of GluR5-IR TG neurons among glutamate-injected, saline-injected, and naive rats, whereas that of TRPV1- or TRPA1-IR TG neurons was significantly increased 7 days after continuous glutamate injection into the facial skin compared with vehicle injection. PKC epsilon phosphorylation in TG was significantly enhanced following glutamate injection into the facial skin. Moreover, neuronal activity of TG neurons was significantly increased following facial glutamate treatment. The present findings suggest that sensitization of TRPA1 and/or TRPV1 through mGluR5 signaling via PKC epsilon is involved in facial thermal and mechanical hypersensitivity.