Article: article from journal or magazin.
JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain.
Journal of Neuroscience
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't Publication Status: ppublish
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.
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
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