Transient receptor potential A1 mediates gastric distention-induced visceral pain in rats
Transient receptor potential A1 mediates gastric distention-induced visceral pain in rats
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DOI：
10.1136/gut.2008.175901
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发表时间：
2009-06
期刊：
影响因子：
24.5
通讯作者：
T. Kondo;K. Obata;Kan Miyoshi;J. Sakurai;J. Tanaka;H. Miwa;Koichi Noguchi
中科院分区：
文献类型：
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作者：
T. Kondo;K. Obata;Kan Miyoshi;J. Sakurai;J. Tanaka;H. Miwa;Koichi Noguchi
背景：瞬时受体电位 (TRP)A1 是 TRP 离子通道家族的成员，已被认为在多种感觉过程中发挥作用，包括热感觉和疼痛。然而，TRPA1 尚未直接涉及胃机械感觉，并且其对胃器官急性内脏疼痛的影响尚不清楚。在这里，我们研究了 TRPA1 在初级感觉传入中的表达及其与大鼠内脏超敏反应的关系。方法：采用免疫组织化学方法检测大鼠背根神经节（DRG）、结状神经节（NG）和胃中 TRPA1 的表达。记录 TRPA1 敲低大鼠和对照大鼠的肩斜方肌对胃扩张 (GD) 的肌电反应。结果：TRPA1 主要在 DRG 和 NG 神经元以及大鼠胃神经纤维中以感觉神经肽表达。刺激后2分钟，胃扩张诱导DRG和NG神经元中细胞外信号调节蛋白激酶1/2（ERK1/2）的激活，并且大多数磷酸化ERK1/2标记的DRG神经元是TRPA1阳性神经元。鞘内注射 TRPA1 反义核酸会减弱内脏运动反应，并抑制 DRG 神经元中的 ERK1/2 激活，但不会抑制 GD 产生的 NG 神经元。此外，鞘内和腹膜内注射 TRPA1 抑制剂 HC-03003 抑制了对有害 GD 的反应。结论：伤害性GD激活DRG神经元中的TRPA1可能与急性内脏痛有关。我们的研究结果表明，TRPA1 在初级传入神经中的潜在阻断可以作为减少内脏超敏反应的新治疗靶点。
Background: Transient receptor potential (TRP)A1, a member of the TRP family of ion channels, has been proposed to function in diverse sensory processes, including thermosensation and pain. However, TRPA1 has not been directly implicated in stomach mechanosensation, and its contribution to acute visceral pain from this organ is unknown. Here, we investigated the expression of TRPA1 in primary sensory afferents and its involvement in visceral hypersensitivity in rats. Methods: We examined TRPA1 expression in the dorsal root ganglion (DRG), nodose ganglion (NG), and stomach of rats by using immunohistochemistry. Electromyographic responses to gastric distention (GD) were recorded from the acromiotrapezius muscle in TRPA1 knockdown rats and in control rats. Results: TRPA1 was predominantly expressed with sensory neuropeptides in DRG and NG neurons, and in nerve fibres in the rat stomach. Gastric distention induced the activation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) in DRG and NG neurons 2 min after stimulation, and most of the phosphorylated-ERK1/2-labelled DRG neurons were TRPA1-positive neurons. Intrathecal injection of TRPA1 antisense attenuated the visceromotor response, and suppressed ERK1/2 activation in the DRG, but not NG, neurons produced by GD. Furthermore, intrathecal and intraperitoneal injections of the TRPA1 inhibitor HC-03003 suppressed the response to noxious GD. Conclusions: The activation of TRPA1 in DRG neurons by noxious GD may be involved in acute visceral pain. Our findings point to the potential blockade of TRPA1 in primary afferents as a new therapeutic target for the reduction of visceral hypersensitivity.