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

• Published in: European journal of pain 2009-09, Vol.13 (8), p.794-806
• Main Authors: Lee, Kyung-Min, Jeon, Sang-Min, Cho, Hee-Jung
• Format: Article
• Language: English
• Subjects: Anesthesia & Perioperative Care; Animals; Behavior, Animal - drug effects; Enzyme Activation - drug effects; Enzyme-Linked Immunosorbent Assay; Ganglia, Spinal - drug effects; Ganglia, Spinal - physiology; Immunohistochemistry; Injections, Spinal; Interleukin-6; Interleukin-6 - biosynthesis; Male; Neuropathic pain mechanism; NF-kappa B - drug effects; NF-κB; Oligonucleotides, Antisense - pharmacology; p38 MAPK; p38 Mitogen-Activated Protein Kinases - metabolism; Pain - etiology; Pain - metabolism; Pain Medicine; Peripheral nerve injury; Peripheral Nervous System Diseases - complications; Peripheral Nervous System Diseases - metabolism; Rats; Rats, Sprague-Dawley; Receptors, Tumor Necrosis Factor, Type I - biosynthesis; Receptors, Tumor Necrosis Factor, Type I - genetics; Receptors, Tumor Necrosis Factor, Type I - physiology; Reverse Transcriptase Polymerase Chain Reaction; Sciatic Nerve - drug effects; Spinal Cord - drug effects; Spinal Cord - physiology; Up-Regulation - drug effects
• ISSN: 1090-3801; 1532-2149
• DOI: 10.1016/j.ejpain.2008.09.009

Abstract Peripheral nerve injury resulting in neuropathic pain induces the upregulation of interleukin (IL)-6 and tumor necrosis factor-α, which binds to tumor necrosis factor receptor 1 (TNFR1) and induces NF-κB and p38 MAPK activation in the spinal cord and dorsal root ganglia (DRG). We here investigated whether TNFR1 regulates IL-6 expression through NF-κB 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-α degradation, the nuclear translocation, phosphorylation, and DNA-binding activity of NF-κB, p38 MAPK activation, and IL-6 mRNA and protein expression in the spinal cord and DRG. Interestingly, CCI remarkably elevated IKKα and p65 phosphorylations in the spinal cord rather than in the DRG. In addition, NF-κB 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-κB, but not p38 MAPK activation in the spinal cord and DRG and that the NF-κB/IL-6 pathways in the DRG may be less dependent on TNFR1 than the spinal cord pathway.