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Blockage of TNF-á receptor-1 reduces neuropathic nociception and spinal cord c-Fos expression after tibia fracture in a rat model of complex regional pain syndrome type I
Ilya Sabsovich, MD/MSc1, Tian-Zhi Guo, MD1, Tzuping Wei, MD1, Xiangqi Li, MD2, David J. Clark, MD/PhD2, Claudia Sommer, MD3, and Wade S. Kingery, MD1. (1) Veterans Affairs Palo Alto Health Care System, Physical Medicine and Rehabilitation Service, 3801 Miranda Avenue, Palo Alto, CA 94304-1290, (2) Anesthesiology, Stanford University, 3801 Miranda Ave., Palo Alto, CA 94304, (3) Department of Neurology, Julius-Maximilians-Universitat, Josef-Schneider-Str. 11, D-97080, Wurzburg, Germany
Tibia fracture in rats evokes chronic hindpaw warmth, edema, allodynia, and periarticular bone loss, a syndrome resembling complex regional pain syndrome type I (CRPS I). Previous studies suggest that the pathogenesis of some of these changes is attributable to an exaggerated regional inflammatory response to injury. We postulated that the pro-inflammatory cytokine tumor necrosis factor alpha (TNFá, an important mediator of chronic neuropathic and inflammatory pain, might also mediate the development of CRPS-like changes after tibia fracture. RT-PCR and EIA assays were used to evaluate changes in TNFá expression and content in skin, nerve, and bone at 4 weeks post-fracture. Bilateral hindpaw thickness, temperature, and nociceptive thresholds were determined, and bone microarchitecture was measured using microcomputed tomography (µCT). In addition, lumbar spinal cord c-Fos immonostaining was performed for quantification of Fos positive neurons. After baseline behavioral testing the distal tibia was fractured and the hindlimb casted for 4 weeks. The rats were subcutaneously injected either with a TNFá receptor antagonist (soluble TNFá receptor type 1, sTNFá-R1, 5mg/kg/d) or saline every 3 days, over 28 days and then were retested at 4-weeks post-fracture. Tibia fracture chronically upregulated TNFá expression and protein levels in the sciatic nerve, hindpaw skin, and proximal tibia. After fracture the rats developed hindpaw mechanical allodynia and unweighting, and these nociceptive behaviors were reversed by sTNFá-R1 treatment. Consistent with the behavioral data, spinal Fos increased after fracture and this effect was inhibited by sTNFá-R1 treatment. Conversely, sTNFá-R1 treatment had no effect on the hindpaw warmth, edema, or periarticular bone loss that developed after tibia fracture. Collectively, these data suggest that facilitated TNFá signaling in the hindlimb is an important mediator of chronic regional nociceptive sensitization after fracture, but is not the major contributor to the hindpaw warmth, edema, and bone loss observed in this CRPS I model.