Anti-HMGB1 neutralization antibody improves pain-related behavior induced by application of autologous nucleus pulposus onto nerve roots in rats

Ken-ichi Otoshi, Shin-ichi Kikuchi, Kinsh Kato, Miho Sekiguchi, Shin-ichi Konno
Spine 2011 May 15, 36 (11): E692-8

STUDY DESIGN: Controlled, interventional, animal study.

OBJECTIVE: To examine the involvement of high-mobility group box 1 (HMGB1) in the neuropathic pain state induced by the application of nucleus pulposus onto the dorsal root ganglion (DRG) and to investigate the effect of HMGB1 neutralization antibody in the pathogenesis.

SUMMARY OF BACKGROUND DATA: HMGB1 is a potent proinflammatory mediator when present extracellularly, and anti-HMGB1 neutralization antibody inhibits inflammation, cytokine expression, and macrophage activation.

METHODS: Thirty-nine adult female Sprague-Dawley rats (200-300 g) were used. The left L5/6 facet joint was removed, and the L5 DRG was exposed. Nucleus pulposus harvested from the tail was applied to the left L5 DRG. Then, 400 μg of anti-HMGB1 neutralization antibody was administered intraperitoneally after surgery. Behavioral testing using von Frey hairs was performed to investigate the mechanical withdrawal threshold. Neuronal damage was investigated by counting the number of activating transcription factor 3 (ATF3) neurons. The expressions of tumor necrosis factor-α (TNF-α) and HMGB1 were measured by double-labeled immunohistochemistry and immunoblotting.

RESULTS: Immunoblotting of harvested nucleus pulposus revealed HMGB1 in the nucleus pulposus. Double-labeled immunohistochemistry revealed that macrophages in the applied nucleus pulposus expressed HMGB1 and TNF-α. Administration of anti-HMGB1 neutralization antibody significantly reduced the TNF-α expression in the DRG and improved the pain-related behavior from day 2 to day 14.

CONCLUSION: HMGB1 appears to play an important role in the development of pain-related behavior induced by the application of nucleus pulposus onto the DRG. HMGB1 from applied nucleus pulposus and actively secreted from macrophages would act as a proinflammatory mediator together with proinflammatory cytokines. HMGB1 blocking therapy might become a new treatment method for neuropathic pain.

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