JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain.
JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain.
复制标题
DOI：
10.1523/jneurosci.3623-08.2009
复制
发表时间：
2009-04-01
期刊：
影响因子：
--
通讯作者：
Ji RR
中科院分区：
文献类型：
--
作者：
Gao YJ;Zhang L;Samad OA;Suter MR;Yasuhiko K;Xu ZZ;Park JY;Lind AL;Ma Q;Ji RR
我们的前期研究表明，脊髓星形胶质细胞中c-jun-N-末端激酶（JNK）的激活在神经病理性疼痛敏化中起重要作用。我们进一步研究了JNK如何调节神经病理性疼痛。在培养的星形胶质细胞中，TNF-α通过TNF受体1瞬时激活JNK。细胞因子芯片显示趋化因子CCL 2/MCP-1（monocyte chemoattractant protein-1）在TNF-α/JNK通路的诱导下表达增强。JNK抑制剂SP 600125和D-JNKI-1剂量依赖性地抑制TNF-α上调MCP-1。脊髓注射TNF-α可引起JNK依赖性疼痛超敏反应和脊髓MCP-1上调。此外，脊髓神经结扎（SNL）诱导持续的神经性疼痛和MCP-1在脊髓中的上调，两者都被D-JNKI-1抑制。值得注意的是，MCP-1主要在SNL后的脊髓星形胶质细胞中诱导。MCP-1中和抗体的脊髓给药减弱了神经性疼痛。相反，MCP-1的脊髓应用诱导热痛觉过敏和浅层脊髓背角神经元中细胞外信号调节激酶（ERK）的磷酸化，指示中枢敏化（背角神经元的过度活跃）。膜片钳记录显示，MCP-1不仅增强自发兴奋性突触电流（sEPSC），但也加强NMDA和AMPA诱导的电流在第二层神经元的分离脊髓切片。最后，MCP-1受体CCR 2在脊髓的神经元和一些非神经元细胞中表达。总之，我们揭示了一个以前未知的MCP-1诱导和作用机制。JNK激活后星形胶质细胞中MCP-1的诱导通过增强兴奋性突触传递促进中枢敏化和神经病理性疼痛。JNK/MCP-1通路的抑制可能为神经病理性疼痛管理提供新的治疗方法。
Our previous study showed that activation of c-jun-N-terminal kinase (JNK) in spinal astrocytes plays an important role in neuropathic pain sensitization. We further investigated how JNK regulates neuropathic pain. In cultured astrocytes, TNF-α transiently activated JNK via TNF receptor-1. Cytokine array indicated that the chemokine CCL2/MCP-1 (monocyte chemoattractant protein-1) was strongly induced by the TNF-α/JNK pathway. MCP-1 upregulation by TNF-α was dose-dependently inhibited by the JNK inhibitors SP600125 and D-JNKI-1. Spinal injection of TNF-α produced JNK-dependent pain hypersensitivity and MCP-1 upregulation in the spinal cord. Further, spinal nerve ligation (SNL) induced persistent neuropathic pain and MCP-1 upregulation in the spinal cord, and both were suppressed by D-JNKI-1. Remarkably, MCP-1 was primarily induced in spinal cord astrocytes after SNL. Spinal administration of MCP-1 neutralizing antibody attenuated neuropathic pain. Conversely, spinal application of MCP-1 induced heat hyperalgesia and phosphorylation of extracellular signal-regulated kinase (ERK) in superficial spinal cord dorsal horn neurons, indicative of central sensitization (hyperactivity of dorsal horn neurons). Patch clamp recordings in lamina II neurons of isolated spinal cord slices showed that MCP-1 not only enhanced spontaneous excitatory synaptic currents (sEPSCs) but also potentiated NMDA- and AMPA-induced currents. Finally, the MCP-1 receptor CCR2 was expressed in neurons and some non-neuronal cells in the spinal cord. Taken together, we have revealed a previously unknown mechanism of MCP-1 induction and action. MCP-1 induction in astrocytes following JNK activation contributes to central sensitization and neuropathic pain facilitation by enhancing excitatory synaptic transmission. Inhibition of the JNK/MCP-1 pathway may provide a new therapy for neuropathic pain management.