Role of transient receptor potential melastatin 2 (TRPM2) channels in visceral nociception and hypersensitivity
Role of transient receptor potential melastatin 2 (TRPM2) channels in visceral nociception and hypersensitivity
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DOI：
10.1016/j.expneurol.2016.09.001
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发表时间：
2016-11-01
影响因子：
5.3
通讯作者：
Horie, Syunji
中科院分区：
文献类型：
--
作者：
Matsumoto, Kenjiro;Takagi, Kanako;Horie, Syunji
瞬时受体电位melastatin 2（TRPM 2）是一种温度敏感的、Ca 2+可渗透的阳离子通道。TRPM 2有助于炎症性肠病以及炎症性和神经性疼痛的发病机制。我们假设TRPM 2对内脏伤害感受和内脏高敏感性的发展是重要的。因此，我们研究TRPM 2通道的表达及其参与内脏伤害性感受在正常生理和病理条件下，导致内脏高敏感性大鼠。TRPM 2在大鼠胃肠道粘膜层和肌层均有表达。TRPM 2免疫阳性细胞体几乎完全共定位与calretinin和NeuN阳性细胞在肌间神经丛。我们发现，大多数的TRPM 2免疫反应性细胞是双标记的逆行标记物荧光金在腰6/骶1背根神经节（DRG），表明TRPM 2表达在脊髓初级传入神经支配远端结肠。TRPM 2免疫阳性DRG神经元的亚型由A纤维标记物NF 200、C纤维标记物IB 4、P物质、降钙素基因相关肽或P2 X3受体标记。我们发现，口服TRPM 2抑制剂益康唑（30 mg/kg）减少内脏反应（VMR）在80毫米汞柱的伤害性结直肠扩张（CRD）在对照组大鼠。在三硝基苯磺酸诱导的结肠炎模型中，远端结肠粘膜中TRPM 2的表达增加。在40、60和80 mm Hg下，结肠炎模型大鼠的VMR至CRD显著增加。益康唑使内脏高敏感性恢复到对照水平。此外，TRPM 2-缺陷型小鼠表现出显着减弱三硝基苯磺酸诱导的内脏高敏感性与野生型小鼠相比。总之，TRPM 2通道有助于内脏伤害性刺激在正常条件下和内脏高敏感性在病理条件下的反应。(C)2016 Elsevier Inc. All rights reserved.
Transient receptor potential melastatin 2 (TRPM2) is a thermosensitive, Ca2+-permeable cation channel. TRPM2 contributes to the pathogenesis of inflammatory bowel disease, and inflammatory and neuropathic pain. We hypothesized that TRPM2 is important for visceral nociception and the development of visceral hypersensitivity. Therefore, we investigated the expression of TRPM2 channels and their involvement in visceral nociception in normal physiology and under pathological conditions that cause visceral hypersensitivity in rats. TRPM2 immunoreactivities were detected in the mucosa and muscle layer of the rat gastrointestinal tract. TRPM2 immunopositive cell bodies were almost completely co-localized with calretinin- and NeuN-positive cells in the myenteric plexus. We found that the majority of the TRPM2-immunoreactive cells were double-labeled with the retrograde marker fluorogold in lumbar 6/sacral 1 dorsal root ganglia (DRG), indicating that TRPM2 is expressed in spinal primary afferents innervating the distal colon. Subtypes of TRPM2-immunopositive DRG neurons were labeled by the A-fiber marker NF200, the C-fiber marker IB4, substance P, calcitonin gene-related peptide, or P2X3 receptor. We found that oral administration of the TRPM2 inhibitor econazole (30 mg/kg) reduced the visceromotor response (VMR) to noxious colorectal distention (CRD) at 80 mm Hg in control rats. Expression of TRPM2 in the mucosa of the distal colon was increased in a trinitrobenzene sulfonic acid-induced colitis model. The VMR to CRD significantly increased in colitis model rats compared with control rats at 40, 60, and 80 mm Hg. Econazole restored visceral hypersensitivity to the control level. Furthermore, TRPM2-deficient mice showed significantly attenuated trinitrobenzene sulfonic acid induced visceral hypersensitivity compared with wild-type mice. In conclusion, TRPM2 channels contribute to visceral nociception in response to noxious stimuli under normal conditions and visceral hypersensitivity in pathological conditions. (C) 2016 Elsevier Inc. All rights reserved.