Activation of Spinal NF-κB/p65 Contributes to Peripheral Inflammation and Hyperalgesia in Rat Adjuvant-Induced Arthritis

Objective. It is known that noxious stimuli from inflamed tissue may increase the excitability of spinal dorsal horn neurons (a process known as central sensitization), which can signal back and contribute to peripheral inflammation. However, the underlying mechanisms have yet to be fully defined. A number of recent studies have indicated that spinal NF-kappa B/p65 is involved in central sensitization, as well as pain-related behavior. Thus, the aim of this study was to determine whether NF-kappa B/p65 can facilitate a peripheral inflammatory response in rat adjuvant-induced arthritis (AIA). Methods. Lentiviral vectors encoding short hairpin RNAs that target NF-kappa B/p65 (LV-shNF-kappa B/p65) were constructed for gene silencing. The spines of rats with AIA were injected with LV-shNF-kappa B/p65 on day 3 or day 10 after treatment with Freund's complete adjuvant (CFA). During an observation period of 20 days, pain-related behavior, paw swelling, and joint histopathologic changes were evaluated. Moreover, the expression levels of spinal tumor necrosis factor alpha (TNF alpha), interleukin-1 beta (IL-1 beta), and cyclooxygenase 2 (COX-2) were assessed on day 14 after CFA treatment. Results. The presence of peripheral inflammation in rats with AIA induced an increase in NF-kappa B/p65 expression in the spinal cord, mainly in the dorsal horn neurons and astrocytes. Delivery of LV-shNF-kappa B/p65 to the spinal cord knocked down the expression of NF-kappa B/p65 and significantly attenuated hyperalgesia, paw edema, and joint destruction. In addition, spinal delivery of LV-shNF-kappa B/p65 reduced the overexpression of spinal TNF alpha, IL-1 beta, and COX-2. Conclusion. These findings indicate that spinal NF-kappa B/p65 plays an important role in the initiation and development of both peripheral inflammation and hyperalgesia. Thus, inhibition of spinal NF-kappa B/p65 expression may provide a potential treatment to manage painful inflammatory disorders.