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TNF signaling contributes to the development of nociceptive sensitization in a tibia fracture model of complex regional pain syndrome type I

Sabsovich, Ilyaa,b; Guo, Tian-Zhia; Wei, Tzupinga; Zhao, Ronga; Li, Xiangqib; Clark, David J.b; Geis, Christianc; Sommer, Claudiac; Kingery, Wade S.a,d,*

doi: 10.1016/j.pain.2007.10.013
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Tibia fracture in rats initiates a cascade of nociceptive, vascular, and bone changes resembling complex regional pain syndrome type I (CRPS I). Previous studies suggest that the pathogenesis of these changes is attributable to an exaggerated regional inflammatory response to injury. We postulated that the pro-inflammatory cytokine tumor necrosis factor alpha (TNF) might mediate the development of CRPS-like changes after fracture. RT-PCR and EIA assays were used to evaluate changes in TNF expression and content in skin, nerve, and bone after fracture. Bilateral hindpaw thickness, temperature, and nociceptive thresholds were determined, and bone microarchitecture was measured using microcomputed tomography. Lumbar spinal cord Fos immunostaining was performed for quantification of Fos positive neurons. After baseline testing, the distal tibia was fractured and the hindlimb casted for 4 weeks. The rats were subcutaneously injected either with a soluble TNF receptor type 1 (sTNF-R1, 5 mg/kg/d) or saline every 3 days over 28 days and then were retested at 4 weeks post-fracture. Tibia fracture chronically upregulated TNF expression and protein levels in the hindpaw skin and sciatic nerve. After fracture the rats developed hindpaw mechanical allodynia and unweighting, which were reversed by sTNF-R1 treatment. Consistent with the behavioral data, spinal Fos increased after fracture and this effect was inhibited by sTNF-R1 treatment. Collectively, these data suggest that facilitated TNF signaling in the hindlimb is an important mediator of chronic regional nociceptive sensitization after fracture, but does not contribute to the hindlimb warmth, edema, and bone loss observed in this CRPS I model.

aPhysical Medicine and Rehabilitation Service (117), Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304, USA

bAnesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, and Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA

cDepartment of Neurology, Julius-Maximilians-Universitat, Wurzburg, Germany

dDepartment of Orthopedic Surgery, Stanford University School of Medicine, Stanford, CA, USA

*Corresponding author. Physical Medicine and Rehabilitation Service (117), Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304, USA. Tel.: +1 650 493 5000x64768; fax: +1 650 852 3470.

E-mail: wkingery@stanford.edu

Submitted June 1, 2007; received in revised form September 27, 2007; accepted October 8, 2007.

© 2008 Lippincott Williams & Wilkins, Inc.
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