Attenuation of colitis-induced visceral hypersensitivity and pain by silencing TRPV1-expressing fibers in rat colon

Abstract

AbstractBackground and AimsAbdominal pain in patients with inflammatory bowel disease (IBD) is common and debilitating. In our study, we aim to utilize transient receptor potential vanilloid 1 (TRPV1) channels, large-pore cation channels expressed on nociceptors, as a drug delivery system to selectively inhibit visceral nociceptors and thus visceral pain in a rodent model of IBD.MethodsWe induced colitis in rats using intrarectal dinitrobenzene sulfonic acid. Visceral hypersensitivity, spontaneous pain, and responsiveness of the hind paws to noxious heat stimuli were examined before and after the intrarectal application of sodium channel blocker QX-314 alone or together with TRPV1 channel activators or blockers.ResultsIntrarectal co-application of QX-314 with TRPV1 channel activator capsaicin significantly inhibited colitis-induced gut hypersensitivity. Furthermore, in the model of colitis, but not in naïve rats, QX-314 alone was sufficient to reverse gut hypersensitivity. The blockade of TRPV1 channels prevented this effect of QX-314. Finally, applying QX-314 alone to the inflamed gut inhibited colitis-induced ongoing pain.ConclusionsSelective silencing of nociceptors by QX-314 entering via exogenously or endogenously activated TRPV1 channels diminish IBD-induced gut hypersensitivity. These results yet again confirm the central role of TRPV1-expressing nociceptive neurons in IBD pain. The lack of QX-314 effect on naïve rats suggests its selective analgesic effect in IBD pain. Moreover, our results demonstrating the effect of QX-314 alone imply the role of a tonically active TRPV1 channel in the pathophysiology of IBD pain. This approach provides proof-of-concept for using charged activity blockers for selective and effective blockade of visceral pain.