Tumor necrosis factor receptor 1 induces interleukin-6 upregulation through NF-kappaB in a rat neuropathic pain model

Peripheral nerve injury resulting in neuropathic pain induces the upregulation of interleukin (IL)-6 and tumor necrosis factor-alpha, which binds to tumor necrosis factor receptor 1 (TNFR1) and induces NF-kappa B and p38 MAPK activation in the spinal cord and dorsal root ganglia (DRG). We here investigated whether TNFR1 regulates IL-6 expression through NF-kappa B or p38 MAPK activations in the spinal cord and DRG in rats with chronic constriction injury (CCI) of the sciatic nerve. Intrathecal treatment with a TNFR1 antisense oligonucleotide (ASO) significantly inhibited CCI-elevated IKKs phosphorylation, IkB-alpha degradation, the nuclear translocation. phosphorylation, and DNA-binding activity of NF-kappa B, p38 MAPK activation, and IL-6 mRNA and protein expression in the spinal cord and DRG. Interestingly, CCI remarkably elevated IKK alpha and p65 phosphorylations in the spinal cord rather than in the DRG. In addition, NF-kappa B decoy, but not p38 MAPK inhibitor, SB203580 reduced CCI-elevated IL-6 expression in the spinal cord and DRG. Therefore, these data suggest that TNFR1 induces IL-6 upregulation and neuropathic pain through NF-kappa B, but not p38 MAPK activation in the spinal cord and DRG and that the NF-kappa B/IL-6 pathways in the DRG may be less dependent on TNFR1 than the spinal cord pathway. (C) 2008 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved.