title: JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain.
abstract: 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.
authors.affiliation: Pain Research Center, Department of Anesthesiology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Yong-Jing
authors.initials: YJ
authors.lastname: Gao
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.forename: Omar Abdel
authors.initials: OA
authors.lastname: Samad
authors.forename: Marc R
authors.initials: MR
authors.lastname: Suter
authors.forename: Kawasaki
authors.initials: K
authors.lastname: Yasuhiko
authors.forename: Zhen-Zhong
authors.initials: ZZ
authors.lastname: Xu
authors.forename: Jong-Yeon
authors.initials: JY
authors.lastname: Park
authors.forename: Anne-Li
authors.initials: AL
authors.lastname: Lind
authors.forename: Qiufu
authors.initials: Q
authors.lastname: Ma
authors.forename: Ru-Rong
authors.initials: RR
authors.lastname: Ji