JNK-Induced MCP-1 Production in Spinal Cord Astrocytes Contributes to Central Sensitization and Neuropathic Pain

• Published in: The Journal of neuroscience Vol. 29; no. 13; pp. 4096 - 4108
• Main Authors: Gao, Yong-Jing, Zhang, Ling, Samad, Omar Abdel, Suter, Marc R, Yasuhiko, Kawasaki, Xu, Zhen-Zhong, Park, Jong-Yeon, Lind, Anne-Li, Ma, Qiufu, Ji, Ru-Rong
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 01.04.2009; Society for Neuroscience
• Subjects: Analysis of Variance; Animals; Astrocytes - drug effects; Astrocytes - metabolism; Cells, Cultured; Chemokine CCL2 - metabolism; Chemokine CCL2 - pharmacology; Cytokines - metabolism; Dose-Response Relationship, Drug; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Enzyme-Linked Immunosorbent Assay - methods; Excitatory Amino Acid Agonists - pharmacology; Glial Fibrillary Acidic Protein - metabolism; Green Fluorescent Proteins - genetics; Indoles - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinase 8 - metabolism; Neuralgia - metabolism; Neuralgia - pathology; Pain Threshold - physiology; Patch-Clamp Techniques - methods; Reaction Time - drug effects; Receptors, CCR2 - genetics; Receptors, CCR2 - metabolism; Receptors, Tumor Necrosis Factor, Type I - deficiency; Spinal Cord - metabolism; Spinal Cord - pathology; Synaptic Transmission - drug effects; Synaptic Transmission - genetics; Time Factors; Tumor Necrosis Factor-alpha - pharmacology; Up-Regulation - drug effects
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.3623-08.2009

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, tumor necrosis factor alpha (TNF-alpha) 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-alpha/JNK pathway. MCP-1 upregulation by TNF-alpha was dose dependently inhibited by the JNK inhibitors SP600125 (anthra[1,9-cd]pyrazol-6(2H)-one) and D-JNKI-1. Spinal injection of TNF-alpha produced JNK-dependent pain hypersensitivity and MCP-1 upregulation in the spinal cord. Furthermore, 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 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 EPSCs 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. Together, we have revealed a previously unknown mechanism of MCP-1 induction and action. MCP-1 induction in astrocytes after 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.