Peripheral Inflammation Accelerates the Onset of Mechanical Hypersensitivity after Spinal Cord Injury and Engages Tumor Necrosis Factor α Signaling Mechanisms.

Abstract

Previously, we showed that noxious stimulation of the tail produces numerous detrimental effects after spinal cord injury (SCI), including an earlier onset and increased magnitude of mechanical hypersensitivity. Expanding on these observations, this study sought to determine whether localized peripheral inflammation similarly impacts the expression of mechanical hypersensitivity after SCI. Adult rats received a moderate contusion injury at the thoracic level (Tl0) or sham surgery, and were administered complete Freund's adjuvant (CFA) or vehicle in one hindpaw 24 hours later. Examination of locomotor recovery (Basso, Beattie, and Bresnahan [BBB] score) showed no adverse effect of CFA. Mechanical testing with von Frey hairs was done at time-points ranging from 1 h to 28 days after CFA or vehicle treatment, and rats were sacrificed at 1, 7, or 28 days for cellular assessment. Unlike vehicle-treated SCI rats where mechanical hypersensitivity emerged at 14 days, CFA-treated SCI rats showed mechanical hypersensitivity as early as 1 h after CFA administration, which lasted at least 28 days. CFA-treated sham subjects also showed an early onset of mechanical hypersensitivity, but this was maintained up to 7 days after treatment. Cellular assessments revealed congruent findings. Expression levels of c-fos, tumor necrosis factor α (TNFα), TNF receptors, and members of the TNFα signaling pathway such as caspase 8 and phosphorylated extracellular related kinase (pERK) were preferentially upregulated in the lumbar spinal cord of SCI-CFA rats. Meanwhile, c-jun was significantly increased in both CFA-treated groups. Overall, these results together with our previous reports, suggest that peripheral noxious input after SCI facilitates the development of pain by mechanisms that may require TNFα signaling.