基于p38MAPK信号通路介导的脊髓P2Y12受体在骨癌痛中的作用和机制

Cancer-induced bone pain (CIBP) is a common clinical cancer pain, which has a high incidence, severe pain. There are still no effective drugs and methods to treat with CIBP. because mechanisms responsible for the induction and maintenance of bone cancer pain are not clearly understood. Currently, it has been one of medicine challenges for strengthen the study of the mechanism of CIBP. Our research group previously study showed that the spinal cord dorsal horn microglia P2Y12 receptor and p38MAPK signaling pathway played an important role in the formation process of bone cancer pain. The aim of this project is to study the expression and relationship of the spinal cord dorsal horn microglia P2Y12 receptor, p38MAPK and inflammatory factors in the formation process of the cancer-induced bone pain rat, investigate that spinal cord microglia P2Y12 receptor in bone cancer pain rat through p38MAPK signaling pathway mediated by the release of inflammatory cytokines, as well as the release of inflammatory cytokines involved in the activation of pain-sensitive neurons or glial cells, thus revealing the molecular mechanisms of cancer-induced bone pain, providing a theoretical basis for the development of a new generation drug of cancer-induced bone pain prevention.

骨癌痛是临床常见的癌症性疼痛，其发病率高、疼痛剧烈。由于骨癌痛发生的机制复杂，目前尚无有效的药物和方法治疗骨癌痛。所以，阐明骨癌痛的机制是迫切需要解决的难题之一。本课题组前期研究发现，脊髓背角小胶质细胞P2Y12受体和p38MAPK信号通路在骨癌痛形成过程中起重要的作用。为此，本项目旨在研究脊髓背角小胶质细胞P2Y12受体、p38MAPK和炎症因子在SD大鼠骨癌痛形成过程中表达的变化及其相互关系，阐明骨癌痛大鼠脊髓小胶质细胞内P2Y12受体通过p38MAPK信号通路介导炎症因子的释放机制，以及炎症因子参与活化痛敏感性神经元/神经胶质细胞的作用，揭示骨癌痛发生的分子机制，为开发新一代的骨癌痛防治药物提供理论依据。

骨癌痛是临床常见的癌症性疼痛，其发病率高、疼痛剧烈。由于骨癌痛发生的机制复杂，目前尚无有效的治疗方法和药物。所以，阐明骨癌痛发生机制是当前迫切需要解决的难题之一。本项目旨在研究脊髓背角小胶质细胞P2Y12受体、p38MAPK和炎症因子在SD大鼠骨癌痛形成过程中表达的变化及其相互关系，阐明骨癌痛大鼠脊髓小胶质细胞内P2Y12受体通过p38MAPK信号通路介导炎症因子的释放机制。本项目研究发现：（1）骨癌痛大鼠痛阈明显降低，脊髓背角P2Y12受体、p-P38MAKP、炎症因子的表达上调，推测脊髓背角P2Y12受体、p-P38MAKP、炎症因子可能参与骨癌痛的形成。（2）P2Y12受体抑制剂可抑制p-P38MAKP的表达上调，揭示脊髓小胶质细胞P2Y12受体可通过p38MAPK信号通路调控骨癌痛的发生和维持。（3）骨癌痛大鼠p-P38MAKP表达于脊髓小胶质细胞，揭示在脊髓水平P2Y12受体通过小胶质细胞调节p-P38MAKP的表达。（4）研究发现P2Y12受体、p38MAPK调节小胶质细胞炎症因子的释放，推测脊髓背角小胶质细胞P2Y12受体是通过p38MAPK信号通路转导胞内疼痛信号并调控细胞炎症因子TNF-α、IL-1β的表达，继而激活周围的神经元，导致骨癌痛的发生和维持。（5）本课题研究成果已发表中华级论文1篇、SCI论文1篇已投；发表项目相关中华级论文2篇、SCI论文1篇；获批新型实用专利1项；培养研究生3 名。