1 Department of Anatomy and Physiology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
2 Department of Radiology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Mol Pain. 2019 Jan-Dec;15:1744806919830018. doi: 10.1177/1744806919830018.
Elevated excitability of primary afferent neurons underlies chronic pain in patients with functional or inflammatory bowel diseases. Recent studies have established an essential role for an enhanced transient receptor potential vanilloid subtype 1 (TRPV1) signaling in mediating peripheral hyperalgesia in inflammatory conditions. Since colocalization of Toll-like receptor 4 (TLR4) and TRPV1 has been observed in primary afferents including the trigeminal sensory neurons and the dorsal root ganglion neurons, we test the hypothesis that TLR4 might regulate the expression and function of TRPV1 in primary afferent neurons in 2,4,6-trinitrobenzene sulfate (TNBS)-induced colitis using the TLR4-deficient and the wild-type C57 mice. Despite having a higher disease activity index following administration of 2,4,6-trinitrobenzene sulfate, the TLR4-deficient mice showed less inflammatory infiltration in the colon than the wild-type mice. Increased expression of TLR4 and TRPV1 as well as increased density of capsaicin-induced TRPV1 current was observed in L4-S2 dorsal root ganglion neurons of the wild-type colitis mice till two weeks post 2,4,6-trinitrobenzene sulfate treatment. In comparison, the TLR4-deficient colitis mice had lower TRPV1 expression and TRPV1 current density in dorsal root ganglion neurons with lower abdominal withdrawal response scores during noxious colonic distensions. In the wild type but not in the TLR4-deficient dorsal root ganglion neurons, acute administration of the TLR4 agonist lipopolysaccharide increased the capsaicin-evoked TRPV1 current. In addition, we found that the canonical signaling downstream of TLR4 was activated in 2,4,6-trinitrobenzene sulfate-induced colitis in the wild type but not in the TLR4-deficient mice. These results indicate that TLR4 may play a major role in regulation of TRPV1 signaling and peripheral hyperalgesia in inflammatory conditions.
原发性传入神经元兴奋性升高是功能性或炎症性肠病患者慢性疼痛的基础。最近的研究已经确立了瞬时受体电位香草酸亚型 1（TRPV1）信号增强在介导炎症条件下外周痛觉过敏中的重要作用。由于 Toll 样受体 4（TLR4）和 TRPV1 在包括三叉神经感觉神经元和背根神经节神经元在内的初级传入纤维中存在共定位，我们使用 TLR4 缺陷型和野生型 C57 小鼠来检验 TLR4 是否可能调节 TRPV1 在 2,4,6-三硝基苯磺酸（TNBS）诱导的结肠炎中初级传入神经元中的表达和功能的假设。尽管在给予 2,4,6-三硝基苯磺酸后疾病活动指数更高，但 TLR4 缺陷型小鼠的结肠炎症浸润程度低于野生型小鼠。在 TNBS 治疗后两周内，野生型结肠炎小鼠的 L4-S2 背根神经节神经元中观察到 TLR4 和 TRPV1 的表达增加以及辣椒素诱导的 TRPV1 电流密度增加。相比之下，TLR4 缺陷型结肠炎小鼠的背根神经节神经元中 TRPV1 表达和 TRPV1 电流密度较低，在有害性结肠扩张时腹部退缩反应评分较低。在野生型而非 TLR4 缺陷型背根神经节神经元中，TLR4 激动剂脂多糖的急性给药增加了辣椒素诱发的 TRPV1 电流。此外，我们发现 TLR4 的经典信号通路在野生型但不在 TLR4 缺陷型小鼠的 TNBS 诱导的结肠炎中被激活。这些结果表明 TLR4 可能在调节 TRPV1 信号和炎症条件下的外周痛觉过敏中起主要作用。
