Jiangsu Key Laboratory of Neuropsychiatric Diseases, Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Suzhou, P.R. China.
People's Hospital of Suzhou National New & Hi-Tech Industrial Development Zone, Suzhou, P.R. China.
Mol Pain. 2020 Jan-Dec;16:1744806920918059. doi: 10.1177/1744806920918059.
Irritable bowel syndrome is one of the most common gastrointestinal disorders. It is featured by abdominal pain in conjunction with altered bowel habits. However, the pathophysiology of the syndrome remains largely unknown. Tumor necrosis factor receptor-associated factor 6 (TRAF6) has been reported to be involved in neuropathic pain. The aim of this study was to investigate roles and mechanisms of TRAF6 in the chronic visceral hypersensitivity.
Visceral hypersensitivity was induced by neonatal colonic inflammation and was identified by colorectal distention. The protein level, RNA level, and cellular distribution of TRAF6 and its related molecules were detected with Western blot, quantitative polymerase chain reaction, and immunofluorescence. In vitro spinal cord slice recording technique was performed to determine the synaptic transmission activities.
Neonatal colonic inflammation rats displayed visceral hypersensitivity at the age of six weeks. The expression of TRAF6 was obviously upregulated in spinal cord dorsal horn of neonatal colonic inflammation rats at the age of six weeks. Immunofluorescence study showed that TRAF6 was dominantly expressed in spinal astrocytes. Intrathecal injection of TRAF6 small interfering RNA (siRNA) significantly reduced the amplitude of spontaneous excitatory postsynaptic currents at the spinal dorsal horn level. Furthermore, knockdown of TRAF6 led to a significant downregulation of cystathionine β synthetase expression in the spinal dorsal horn of neonatal colonic inflammation rats. Importantly, intrathecal injection of TRAF6 siRNA remarkably alleviated visceral hypersensitivity of neonatal colonic inflammation rats.
Our results suggested that the upregulation of TRAF6 contributed to visceral pain hypersensitivity, which is likely mediated by regulating cystathionine β synthetase expression in the spinal dorsal horn. Our findings suggest that TRAF6 might act as a potential target for the treatment of chronic visceral pain in irritable bowel syndrome patients.
肠易激综合征是最常见的胃肠道疾病之一。其特征为腹痛伴排便习惯改变。然而，该综合征的病理生理学仍知之甚少。肿瘤坏死因子受体相关因子 6（TRAF6）已被报道参与神经性疼痛。本研究旨在探讨 TRAF6 在慢性内脏高敏中的作用和机制。
通过新生结肠炎症诱导内脏高敏感，通过直肠扩张鉴定。采用 Western blot、定量聚合酶链反应和免疫荧光检测 TRAF6 及其相关分子的蛋白水平、RNA 水平和细胞分布。采用体外脊髓切片记录技术测定突触传递活动。
新生结肠炎症大鼠在 6 周龄时表现出内脏高敏感。在 6 周龄新生结肠炎症大鼠脊髓背角 TRAF6 的表达明显上调。免疫荧光研究显示 TRAF6 主要在脊髓星形胶质细胞中表达。鞘内注射 TRAF6 小干扰 RNA（siRNA）显著降低脊髓背角自发性兴奋性突触后电流的幅度。此外，TRAF6 敲低导致新生结肠炎症大鼠脊髓背角胱硫醚β合成酶表达明显下调。重要的是，鞘内注射 TRAF6 siRNA 显著减轻新生结肠炎症大鼠的内脏高敏感。
我们的结果表明，TRAF6 的上调导致内脏痛敏，这可能是通过调节脊髓背角胱硫醚β合成酶的表达来介导的。我们的研究结果表明，TRAF6 可能是治疗肠易激综合征患者慢性内脏疼痛的潜在靶点。
