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Objective The N-methyl-D-aspartate receptor (NMDAR) in the superficial dorsal horn is implicated as a major contributor to excitatory transmission.Recent studies suggest NMDAR also contributes to neuron-astrocyte signaling.This study was performed to elucidate the molecular mechanisms underlying spinal NMDAR-mediated c-Jun N-terminal kinase (JNK) activation in neuropathic pain.Methods Animal pain behaviors were evaluated with von-Frey filaments.The cellular distribution of JNK, NR2B receptor, and interleukin-1β was detected by immunofluorescent double staining.JNK activation after different treatments was checked by Western blot analysis.Real-time RT-PCR was performed to detect the changes of cytokines mRNA expression.Results After spinal nerve ligation (SNL), the expression of pJNK and GFAP was significantly higher in the ipsilateral dorsal horn.pJNK was found to be completely colocalized with GFAP.Intrathecal injection of MK-801, a noncompetitive NMDAR antagonist, or Ro25-6981 and ifenprodil, selective antagonists of NR2B subunit, each significantly reduced JNK activation.NR2B was exclusively expressed on neurons, indicating an intercellular effect of NMDAR antagonists on JNK activation.Intrathecal injection of NMDA (twice a day for 3 d) significantly increased JNK phosphorylation.Furthermore, NMDAR-related JNK activation could be blocked by nNOS selective inhibitor 7-nitroindazole sodium salt but not by nNOS sensitive guanylyl cyclase inhibitors.Finally, nerve injury-induced interleukin-lbeta expression was dependent on astrocytic JNK activation.Treatments targeting NMDAR-nNOS pathway also influenced interleukin lbeta expression.Conclusion Our results suggest a signal transduction cascade combining neuronal NMDAR-nNOS pathway with astrocytic JNK pathway, by which excitatory neuronal transmission and astrocytic activation-induced neuroinflammation are linked, contributing to nerve injury-induced neuropathic pain.