TLR4信号转导通路介导的免疫反应在术后急慢性疼痛转化中的作用

Looking for the pathogenesis and new regulative target spot of the conversion from acute pain to chronic pain is the current research focus. The proliferation and activation of the glial cells is considered to be one of the key mechanisms of chronic pain. . The study confirmed: Toll-like receptor-4 (TLR4) is widely distributed in the surface of the spinal cord glial cells and the primary afferent neuron, which endogenous ligand can be released under conditions of Surgical stress, but whether the immune response mediated by TLR4 signaling pathway involved in the proliferation and activation of the glial cells and the role in the Conversion of acute pain to chronic pain is not clear.We found: The mRNA and protein of TLR4, IL-1 β, TNF- α expression in the spinal cord was significantly higher on Cutting Pain in Rats with the Hind Paw Incision, Hyperalgesia and spinal glial activation was also discovered in the early stage of the operation, we speculated that TLR4 signal pathway may be involved in the activation of the glial cells after operation.. According to this hypothesis,we observe the changes of TLR4 signal transduction pathway protein,glial cell marker protein and pain behavior in the persistent postoperative pain (skin/muscle incision and retraction, SMIR) model under the intervention of TLR4 Signal Pathway,to identify the role and relationship of the TLR4 signaling pathway and glial cells activation in SMIR model rats, looking for the new therapeutic targets for blocking the conversion from acute pain to chronic pain.

寻找术后急慢性疼痛的转化机制及调控靶点是当前研究的热点。神经胶质细胞的增殖活化被认为是慢性疼痛产生的关键机制之一，文献证实：Toll样受体-4(TLR4)在神经胶质细胞以及神经元表面广泛分布，手术创伤是引起其内源性配体释放的重要途径，但TLR4信号通路介导的免疫反应是否参与神经胶质细胞的活化增殖以及在术后急慢性疼痛转化中的作用尚不清楚。我们发现：足底切割模型小鼠（急性疼痛）的脊髓及切口周围组织TLR4、IL-1β、TNF-α的mRNA和蛋白表达明显升高，文献亦证实:术后早期小鼠脊髓胶质细胞即发生活化，我们推测，TLR4信号通路可能参与术后神经胶质细胞的活化。据此，我们通过建立持续性术后疼痛模型，针对TLR4信号通路进行干预，观察TLR4信号通路及胶质细胞蛋白的表达及行为学变化；阐明TLR4信号通路在术后急慢性疼痛转化过程中的作用，为阻断术后急慢性疼痛转化提供新的治疗靶点。

持续性术后痛是术后重要的并发症，对病人危害大，严重降低了病人的生活质量。近年来，微炎症持续状态或亚临床炎症在慢性疾病转化过程中的作用越来越受到重视，TLR4(Toll Like Recepter 4)信号通路是重要的炎症通路之一，与许多疾病的发生发展密切相关，其激活引起的下游一系列信号级联反应使疾病朝着不良的方向转化，是目前研究领域的热点。但是目前关于TLR4信号通路在持续性术后痛中的发生机制还不明确。本研究分别在脊髓和脊髓背根神经节两个水平探讨TLR4信号通路在持续性术后疼痛模型大鼠中的作用。研究结果显示：SMIR模型介导了大鼠术侧足底的机械性痛觉过敏，在脊髓水平，SMIR模型介导了TLR4激活，活化后的TLR4激活下游的NF-KB, 活化后的p-p65调节了小胶质细胞的活化，增加了CD11b蛋白的表达。在DRG水平，SMIR模型介导了TLR4激活，活化后的TLR4激活下游的NF-KB, 活化后的p-p65通过调控Nav1.7的基因转录介导了Nav1.7蛋白的高表达。TLR4在脊髓和脊髓背根神经节两个水平分别参与了SMIR介导的慢性术后痛的过程。