脊髓NRG1-ErbB-JNK信号通路在星形胶质细胞调控膀胱疼痛综合症的作用机制

Several researches show that central sensitization plays an important role in the pathogenesis of bladder pain syndrome (BPS), but its mechanism remain unclear. We have revealed, in our previous research, that C-nerve fibers in bladders of patients with BPS increased and which was corresponding to the symptom of pain. Furthermore, activation of astrocytes was observed in spinal dorsal horn of animal models, and suppression of its activation leaded to a relief of pain. In addition, our preliminary experiments utilizing animal models showed an increased expression of neuregulin-1(Nrg1) in spinal cord and antagonizing ErbB, which is its receptor, can relieve the pain. Moreover, our preceding study revealed an increased expression of p-JNK and inflammatory factors, and it has been suggested that inflammatory factors take part in the production and maintenance of pain signal. Thus, we hypothesize that Nrg1 binding ErbB receptor on astrocytes can active the intracellular JNK pathway and release the inflammatory factors, which may involve in the regulation of pain in BPS. This study intends to reveal the role of Nrg1-ErbB pathway in BPS, and further to make clear whether Nrg1-ErbB takes part in the activation of JNK pathway in astrocyte and the release of inflammatory factor, and to investigate the role of Nrg1-ErbB pathway in regulation of bladder pain in BPS. This study will originally reveal a new mechanism of central sensitization induced BPS progression and development, and also provide a new target for the treatment of BPS.

研究表明中枢敏化在膀胱疼痛综合症（BPS）发病中起重要作用，机制不清。前期工作中，我们发现BPS患者膀胱壁C神经纤维增多且与疼痛成正相关;同时发现BPS动物模型脊髓背角星形胶质细胞活化，抑制其活化可缓解疼痛。此外，预实验发现BPS动物模型脊髓神经调节蛋白1（Nrg1）表达增多，拮抗其受体ErbB可减轻BPS疼痛；我们还发现BPS动物模型脊髓p-JNK和炎性因子表达增多,而研究表明炎性因子参与疼痛信号的产生与维持。因此，我们提出Nrg1通过结合星形胶质细胞上的ErbB受体而激活其胞内JNK通路，释放炎性因子而参与BPS疼痛调控的假说。我们将进一步明确Nrg1-ErbB通路在BPS中的作用，以及Nrg1-ErbB是否参与星形胶质细胞内JNK通路活化和炎性因子分泌，明确此信号通路是否参与BPS膀胱疼痛的调控。本课题将从中枢神经敏化的角度揭示BPS发生发展的新机制，为BPS的治疗提供新的靶点。

背景：中枢敏化在环磷酰胺（CYP）引起的膀胱炎中起重要作用。此外，CYP诱发的慢性内脏疼痛与神经性疼痛具有共同的病理生理机制。研究表明，neuregulin-1（Nrg1）-ErbB信号传导会导致神经性疼痛，但尚不清楚该信号传导是否以及如何影响CYP诱导的膀胱炎的机械性异常性疼痛。本研究旨在确定在CYP诱导的膀胱炎大鼠模型中Nrg1-ErbB信号是否以及如何调节机械性异常性疼痛。方法：采用CYP全身注射建立大鼠膀胱疼痛综合征/间质性膀胱炎（BPS/IC）模型。鞘内注射不可逆的ErbB家族受体抑制剂PD168393和外源性Nrg1以调节Nrg1-ErbB信号传导。使用上-下法用von-Frey丝评估下腹部机械性异常性疼痛。免疫印迹分析和免疫荧光染色用于测量L6-S1脊髓背角（SDH）中Nrg1-ErbB信号以及Iba-1、p-p38和IL-1β的表达。结果：我们在膀胱炎组SDH中观察到Nrg1-ErbB信号的上调以及小胶质细胞激活标记Iba-1和p-p38以及促炎因子白介素-1β（IL-1β）的过表达。此外，PD168393的治疗可减轻CYP诱导的膀胱炎的机械异常性疼痛并抑制小胶质细胞活化，从而导致IL-1β的产生减少。抑制剂PD168393逆转了外源性Nrg1对膀胱炎模型的促痛作用。结论：Nrg1-ErbB信号通路可能促进小胶质细胞活化，从而参与了CYP诱导的膀胱炎的机械性异常性疼痛的发生发展。我们的研究表明，调节Nrg1-ErbB信号传导可能对治疗BPS/IC的疼痛症状具有治疗价值。

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