PMID- 19339605 OWN - NLM STAT- MEDLINE DCOM- 20090423 LR - 20220331 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 29 IP - 13 DP - 2009 Apr 1 TI - JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain. PG - 4096-108 LID - 10.1523/JNEUROSCI.3623-08.2009 [doi] AB - 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. FAU - Gao, Yong-Jing AU - Gao YJ AD - Pain Research Center, Department of Anesthesiology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. FAU - Zhang, Ling AU - Zhang L FAU - Samad, Omar Abdel AU - Samad OA FAU - Suter, Marc R AU - Suter MR FAU - Yasuhiko, Kawasaki AU - Yasuhiko K FAU - Xu, Zhen-Zhong AU - Xu ZZ FAU - Park, Jong-Yeon AU - Park JY FAU - Lind, Anne-Li AU - Lind AL FAU - Ma, Qiufu AU - Ma Q FAU - Ji, Ru-Rong AU - Ji RR LA - eng GR - R01 NS054932/NS/NINDS NIH HHS/United States GR - R01 DE013843/DE/NIDCR NIH HHS/United States GR - TW7180/TW/FIC NIH HHS/United States GR - R03 TW007180-03/TW/FIC NIH HHS/United States GR - R03 TW007180/TW/FIC NIH HHS/United States GR - DE17794/DE/NIDCR NIH HHS/United States GR - R01 NS054932-03/NS/NINDS NIH HHS/United States GR - R01 DE018025/DE/NIDCR NIH HHS/United States GR - R01 DE017794/DE/NIDCR NIH HHS/United States GR - NS54932/NS/NINDS NIH HHS/United States GR - R01 NS047710/NS/NINDS NIH HHS/United States GR - R01 DE017794-03/DE/NIDCR NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (Ccl2 protein, mouse) RN - 0 (Ccr2 protein, mouse) RN - 0 (Chemokine CCL2) RN - 0 (Cytokines) RN - 0 (Enzyme Inhibitors) RN - 0 (Excitatory Amino Acid Agonists) RN - 0 (Glial Fibrillary Acidic Protein) RN - 0 (Indoles) RN - 0 (Receptors, CCR2) RN - 0 (Receptors, Tumor Necrosis Factor, Type I) RN - 0 (Tnfrsf1a protein, mouse) RN - 0 (Tumor Necrosis Factor-alpha) RN - 147336-22-9 (Green Fluorescent Proteins) RN - 47165-04-8 (DAPI) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 8) SB - IM MH - Analysis of Variance MH - Animals MH - Astrocytes/drug effects/*metabolism MH - Cells, Cultured MH - Chemokine CCL2/*metabolism/pharmacology MH - Cytokines/metabolism MH - Dose-Response Relationship, Drug MH - Enzyme Activation/drug effects MH - Enzyme Inhibitors/pharmacology MH - Enzyme-Linked Immunosorbent Assay/methods MH - Excitatory Amino Acid Agonists/pharmacology MH - Glial Fibrillary Acidic Protein/metabolism MH - Green Fluorescent Proteins/genetics MH - Indoles/metabolism MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Mitogen-Activated Protein Kinase 8/*metabolism MH - Neuralgia/*metabolism/*pathology MH - Pain Threshold/*physiology MH - Patch-Clamp Techniques/methods MH - Reaction Time/drug effects MH - Receptors, CCR2/genetics/metabolism MH - Receptors, Tumor Necrosis Factor, Type I/deficiency MH - Spinal Cord/metabolism/*pathology MH - Synaptic Transmission/drug effects/genetics MH - Time Factors MH - Tumor Necrosis Factor-alpha/pharmacology MH - Up-Regulation/drug effects PMC - PMC2682921 MID - NIHMS105045 EDAT- 2009/04/03 09:00 MHDA- 2009/04/25 09:00 PMCR- 2009/10/01 CRDT- 2009/04/03 09:00 PHST- 2009/04/03 09:00 [entrez] PHST- 2009/04/03 09:00 [pubmed] PHST- 2009/04/25 09:00 [medline] PHST- 2009/10/01 00:00 [pmc-release] AID - 29/13/4096 [pii] AID - 3469116 [pii] AID - 10.1523/JNEUROSCI.3623-08.2009 [doi] PST - ppublish SO - J Neurosci. 2009 Apr 1;29(13):4096-108. doi: 10.1523/JNEUROSCI.3623-08.2009.