脊髓警报素IL-33/ST2信号轴参与中枢卒中后疼痛的发生与维持

Central post stroke pain (CPSP) is an intractable neuropathic pain, which severely affects the living quality of patients. To date, the underlying mechanisms remains unknown as the basic research is rare. We previously established thalamic hemorrhage-induced experimental CPSP and identified that neuroinflammation in the central nervous system (CNS) was a key factor in the pathogenesis. Our latest studies revealed that the alarmin IL-33 was significantly up-regulated in the spinal cord after thalamic hemorrhage, accompanying with glial activation, neuronal hyperactivity and central sensitization. And blocked of spinal IL-33/ST2 signaling could efficiently reverse the CPSP, suggesting a critical role of IL-33/ST2 signaling in the development and maintenance of CPSP. Based on these results, we hypothesized that spinal IL-33 was secreted as an alarmin once thalamus was injured and which induced neuroinflammatory reaction and central sensitization in the spinal cord through ST2 receptor, eventually resulting in the initiation and maintenance of CPSP. In the present study, we aim to explore the cellular and molecular mechanisms of CPSP by using multiple methods. It is expected to provide theoretic basis for the pathogenesis and new targets for the treatment of CPSP.

中枢卒中后疼痛（Central post stroke pain, CPSP）是一类最顽固的慢性中枢神经病理性痛，严重影响患者的生活质量。到目前为止，其发病机制依然不清。我们前期成功建立了丘脑出血性卒中后疼痛的大鼠模型，并发现神经炎症可能是其发病的关键因素。课题组最新的研究结果显示：CPSP大鼠脊髓内的警报素IL-33表达上调，伴随胶质细胞激活、神经元活化以及中枢敏化形成，而抑制IL-33/ST2信号轴能有效翻转大鼠的痛敏行为，提示警报素IL-33/ST2信号轴参与CPSP的发病。据此，我们提出假说“脊髓内IL-33在丘脑损伤后作为警报素大量合成并释放，作用于ST2受体，一方面激活胶质细胞诱发神经炎症，另一方面活化神经元引起中枢敏化，最终导致CPSP的发生与维持”。为论证该假说，本课题采用多种手段，从分子、细胞到动物水平展开研究，为阐明CPSP发病机制提供理论基础，更为临床防治提供新靶点。

中枢卒中后疼痛（Central post stroke pain, CPSP）是一类最顽固的慢性中枢神经病理性痛，严重影响患者的生活质量。到目前为止，其发病机制依然不清，缺乏有效的治疗药物和手段。前期研究中我们成功建立并评价了丘脑出血引起的CPSP大鼠模型。因此本研究立足于改模型，综合运用行为学、分子生物学和药理学等多种方法，开展了如下研究：（1）CPSP大鼠脊髓IL-33/ST2表达的时空变化及其在CPSP中的作用；（2）脊髓警报素IL-33/ST2信号轴参与CPSP的下游细胞分子机制；（3）星状神经节阻滞治疗CPSP的效果。研究结果发现：（1）CPSP大鼠脊髓IL-33/ST2表达持续上调，IL-33主要来源于脊髓背角神经元；ST2广泛分布于神经元和星形胶质细胞表面；鞘内注射中和性抗体阻断IL-33/ST2信号显著抑制CPSP；（2）CPSP大鼠脊髓背角神经元和胶质细胞持续活化，表现为c-Fos、Iba-1和GFAP表达持续上调；鞘内注射胶质细胞抑制剂显著缓解CPSP，提示脊髓内神经炎症参与CPSP的发生；鞘内鞘内注射中和性抗体阻断IL-33/ST2信号显著抑制CPSP大鼠脊髓内的神经元活化以及胶质细胞激活，提示脊髓IL-33/ST2信号轴通过调控神经元和胶质细胞参与CPSP的发生；（3）连续星状神经节阻滞既能抑制CPSP的发生也可以翻转CPSP的维持。通过本研究的完成，我们阐明了脊髓警报素IL-33/ST2信号在CPSP发生中的作用，深入揭示了IL-33/ST2信号轴调控神经元和神经胶质细胞的机制，并发现星状神经节阻滞显著缓解CPSP的发生与维持，本研究为CPSP的临床防治提供了新的干预靶点和干预策略。在本基金的资助下，发表SCI论文4篇。同时，课题组也获得了一些尚未发表的研究成果，推动课题后续进展。