title: Inhibition of IL-6 signaling: A novel therapeutic approach to treating spinal cord injury pain.
abstract: To characterize the contribution of interleukin-6 (IL-6) to spinal cord injury pain (SCIP), we employed a clinically relevant rat contusion model of SCIP. Using Western blots, we measured IL-6 levels in lumbar segments (L1-L5), at the lesion site (T10), and in the corresponding lumbar and thoracic dorsal root ganglia (DRG) in 2 groups of similarly injured rats: (a) SCI rats that developed hind-limb mechanical allodynia (SCIP), and (b) SCI rats that did not develop SCIP. Only in SCIP rats did we find significantly increased IL-6 levels. Immunocytochemistry showed elevated IL-6 predominantly in reactive astrocytes. Our data also showed that increased production of IL-6 in hyperreactive astrocytes in SCIP rats may explain still-poorly understood astrocytic contribution to SCIP. To test the hypothesis that IL-6 contributes to mechanical allodynia, we treated SCIP rats with neutralizing IL-6 receptor antibody (IL-6-R Ab), and found that one systemic injection abolished allodynia and associated weight loss; in contrast to gabapentin, the analgesic effect lasted for at least 2weeks after the injection, despite the shorter presence of the Ab in the circulation. We also showed that IL-6-R Ab partially reversed SCI-induced decreases in the protein levels of the glutamate transporter GLT-1 12hours and 8days after Ab injection, which may explain the lasting analgesic effect of the Ab in SCIP rats. A link between reactive astrocytes IL-6-GLT-1 has not been previously shown. Given that the humanized IL-6-R Ab tocilizumab is Food and Drug Administration-approved for rheumatoid arthritis, we are proposing tocilizumab as a novel and potentially effective treatment for SCIP.
authors: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555-1072, USA.
authors: Jutatip
authors: J
authors: Guptarak
authors: Sheshali
authors: S
authors: Wanchoo
authors: Julieann
authors: J
authors: Durham-Lee
authors: Yewen
authors: Y
authors: Wu
authors: Dragoslava
authors: D
authors: Zivadinovic
authors: Adriana
authors: A
authors: Paulucci-Holthauzen
authors: Olivera
authors: O
authors: Nesic
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015850:Interleukin-6; C502936:tocilizumab