Analgesic effect of resveratrol on colitis-induced visceral pain via inhibition of TRAF6/NF-κB signaling pathway in the spinal cord

Abstract

Visceral pain is a complex and common symptom of inflammatory bowel disease (IBD) patients. Developing novel efficient therapeutics is still a common interest for clinicians. Increasing evidence have shown that tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6) contributes to the pathological pain state in some pain models. Resveratrol (RSV) has showed promising potential for the treatment of neuropathic pain and inflammatory pain. However, whether RSV has analgesic effect on visceral pain and the underlying mechanisms remain unclear. In this study, we established the colitis model through intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS), and found that TNBS induced colonic inflammation and visceral hypersensitivity. Meanwhile, astroglial marker glial fibrillary acidic protein (GFAP), TRAF6, phosphorylation of NF-κB (pNF-κB), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels were increased in L6-S1 spinal cord after TNBS enema. Then, intrathecal injection of TRAF6 siRNA attenuated visceral pain, blocked the upregulation of pNF-κB, TNF-α and IL-1β levels in the spinal cord in TNBS mice. Furthermore, spinal administration of NF-κB inhibitor, BAY11-7082 reversed the pain behavior and suppressed spinal TNF-α and IL-1β expression in TNBS mice. Finally, repeated intrathecal injection of RSV reversed TNBS-induced visceral pain hypersensitivity in a dose-dependent manner. Meanwhile, TNBS-induced enhancement of spinal GFAP, TRAF6, pNF-κB, TNF-α and IL-1β were reduced by the same treatment of RSV. In conclusion, our results suggest that RSV exerts the effects of antinociception on colitis-induced visceral hyperalgesia through inhibition of spinal TRAF6/NF-κB signaling pathway and the production of inflammatory mediators in the spinal cord, suggesting a new application of RSV for the treatment of visceral pain.