The Journal of Neuroscience, April 1, 2009, 29(13):4096-4108; doi:10.1523/JNEUROSCI.3623-08.2009
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Cellular/Molecular
JNK-Induced MCP-1 Production in Spinal Cord Astrocytes Contributes to Central Sensitization and Neuropathic Pain
Yong-Jing Gao,1
Ling Zhang,1
Omar Abdel Samad,2
Marc R. Suter,1
Kawasaki Yasuhiko,1
Zhen-Zhong Xu,1
Jong-Yeon Park,1
Anne-Li Lind,1
Qiufu Ma,2 and
Ru-Rong Ji1
1Pain Research Center, Department of Anesthesiology, Brigham and Women's Hospital, and 2Dana-Farber Cancer Institute and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115
Correspondence should be addressed to Ru-Rong Ji, Department of Anesthesiology, Brigham and Women's Hospital, 75 Francis Street, Medical Research Building, Room 604, Boston, MA 02115. Email: rrji{at}zeus.bwh.harvard.edu
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 
(TNF-) 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-/JNK pathway. MCP-1 upregulation by TNF- 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- 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.
Received July 31, 2008;
revised Feb. 19, 2009;
accepted Feb. 21, 2009.
Correspondence should be addressed to Ru-Rong Ji, Department of Anesthesiology, Brigham and Women's Hospital, 75 Francis Street, Medical Research Building, Room 604, Boston, MA 02115. Email: rrji{at}zeus.bwh.harvard.edu
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F. A. White, P. Feldman, and R. J. Miller
Chemokine Signaling and the Management of Neuropathic Pain
Mol. Interv.,
August 1, 2009;
9(4):
188 - 195.
[Abstract]
[Full Text]
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