背根神经节(DRG)神经元的过度激活与骨癌痛的发生和维持密切相关，TNF-α为调控DRG神经元活化的核心分子，主要通过NF-κB/uPA/PAR2信号通路激活。消癥止痛方是名老中医段凤舞教授国内率先应用中医外治法治疗癌痛的有效方，我们前期的结果显示，消癥止痛方可抑制DRG神经元PAR2/TRPV1及 c-fos的表达发挥镇癌痛作用。但其主要作用途径不明。鉴此，我们提出假说：消癥止痛方通过调控TNF-α介导的NF-κB/uPA/PAR2信号通路，发挥治疗骨癌痛的作用。本项目拟以骨癌痛动物模型为研究载体，以DRG神经元活化的核心分子TNF-α为切入点，通过基因过表达以及基因敲除的双向调控模式，多层次、多角度阐明骨癌痛发生的分子机制；并以此为平台，明确消癥止痛方治疗骨癌痛的主要途径。我们的结果将为寻找抗骨癌痛药物提供新的分子靶点，还为研究中医外治法治疗骨癌痛的作用机制探索新途径。

Excessive activation of dorsal root ganglion (DRG) neurons is crucial for the development of bone cancer pain. TNF-α is the key factor that regulates the excitability of DRG neurons and NF-κB/uPA/PAR2 is the main pathway that regulates the excitability of DRG neurons. Our previous studies have shown that Xiaozhen Zhitong Paste (XZP) we generated based on regulating "circulation network" and detoxification relieve early acute bone cancer pain in patients. It's main mechanism of relieving acute pain is because of inhibiting expression of PAR2/TRPV1 signal pathway in DRG neurons and downregulation of c-fos in spinal cord. Accoridngly, we hypothesize that the therapeutic effect of XZP may regulate the NF-κB/uPA/PAR2 signal pathway regulated by TNF-α, leading to relief of bone cancer pain. We will employ mice model of bone cancer pain and breast cancer cells, and study the mechanism of TNF-α to reveal molecualr mechanisms underlying the anti-pain therapeutic effect of XZP using gene overexpression and gene knockdown skills. Potentially, our findings may reveal new therapuetic targets and aid in the design of new therapies for the intervention of bone cancer pain in humans. Our findings may also probide new scientific basis for understanding the role of external traditional Chinese medicines for the treatment of bone cancer pain.