PDF(Pubmed)
Abstract：
Cancer-induced bone pain (CIBP) is one of the most common and feared symptoms in patients with advanced tumors. The X-C motif chemokine ligand 12 (CXCL12) and the CXCR4 receptor have been associated with glial cell activation in bone cancer pain. Moreover, mitogen-activated protein kinases (MAPKs), as downstream CXCL12/CXCR4 signals, and c-Jun, as activator protein AP-1 components, contribute to the development of various types of pain. However, the specific CIBP mechanisms remain unknown. Esketamine is a non-selective N-methyl-d-aspartic acid receptor (NMDA) inhibitor commonly used as an analgesic in the clinic, but its analgesic mechanism in bone cancer pain remains unclear. We used a tumor cell implantation (TCI) model and explored that CXCL12/CXCR4, p-MAPKs, and p-c-Jun were stably up-regulated in the spinal cord. Immunofluorescence images showed activated microglia in the spinal cord on day 14 after TCI and co-expression of CXCL12/CXCR4, p-MAPKs (p-JNK, p-ERK, p-p38 MAPK), and p-c-Jun in microglia. Intrathecal injection of the CXCR4 inhibitor AMD3100 reduced JNK and c-Jun phosphorylations, and intrathecal injection of the JNK inhibitor SP600125 and esketamine also alleviated TCI-induced pain and reduced the expression of p-JNK and p-c-Jun in microglia. Overall, our data suggest that the CXCL12/CXCR4-JNK-c-Jun signaling pathway of microglia in the spinal cord mediates neuronal sensitization and pain hypersensitivity in cancer-induced bone pain and that esketamine exerts its analgesic effect by inhibiting the JNK-c-Jun pathway.
摘要：
癌症引起的骨痛（CIBP）是晚期肿瘤患者最常见和最担心的症状之一。X-C基序趋化因子配体12（CXCL12）和CXCR4受体与骨癌疼痛中的神经胶质细胞活化有关。此外，丝裂原活化蛋白激酶（MAPK），作为下游CXCL12/CXCR4信号，还有c-Jun,作为激活蛋白AP-1成分，有助于各种类型的疼痛的发展。然而,具体的CIBP机制尚不清楚.Esketamine是一种非选择性的N-甲基-D-天冬氨酸受体（NMDA）抑制剂，通常在临床上用作镇痛药，但其在骨癌疼痛中的镇痛机制尚不清楚。我们使用肿瘤细胞植入（TCI）模型，探索CXCL12/CXCR4，p-MAPK，和p-c-Jun在脊髓中稳定上调。免疫荧光图像显示TCI后第14天脊髓中的小胶质细胞活化，CXCL12/CXCR4，p-MAPK共表达（p-JNK，p-ERK,p-p38MAPK），和小胶质细胞中的p-c-Jun。鞘内注射CXCR4抑制剂AMD3100减少了JNK和c-Jun磷酸化，鞘内注射JNK抑制剂SP600125和艾氯胺酮也减轻了TCI引起的疼痛，并降低了小胶质细胞中p-JNK和p-c-Jun的表达。总的来说,我们的数据提示,脊髓小胶质细胞CXCL12/CXCR4-JNK-c-Jun信号通路介导癌性骨痛中的神经元致敏和疼痛超敏反应,而艾氯胺酮通过抑制JNK-c-Jun通路发挥镇痛作用.
