Attenuation of Colitis-Induced Visceral Hypersensitivity and Pain by Selective Silencing of TRPV1-Expressing Fibers in Rat Colon.

BACKGROUND

Transient receptor potential vanilloid 1 (TRPV1) cation channels, expressed on nociceptors, are well established as key contributors to abdominal pain in inflammatory bowel disease (IBD). Previous attempts at blocking these channels have been riddled with side effects. Here, we propose a novel treatment strategy, utilizing the large pore of TRPV1 channels as a drug delivery system to selectively inhibit visceral nociceptors.

METHODS

We 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 membrane-impermeable sodium channel blocker (QX-314) alone or together with TRPV1 channel activators or blockers.

RESULTS

Intrarectal 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.

CONCLUSIONS

Selective silencing of gut nociceptors by a membrane-impermeable sodium channel blocker entering via exogenously or endogenously activated TRPV1 channels diminishes IBD-induced gut hypersensitivity. The lack of effect on naïve rats suggests a selective analgesic effect in the inflamed gut. Our results suggest that in the colitis model, TRPV1 channels are tonically active. Furthermore, our results emphasize the role of TRPV1-expressing nociceptive fibers in colitis-induced pain. These findings provide proof of concept for using charged activity blockers for the blockade of IBD-associated abdominal pain.

Here, we show that the selective silencing of a specific subtype of nociceptive neurons innervating the gut mitigates colitis-induced visceral hypersensitivity and pain. Our results provide a basis for developing effective and selective treatments for inflammatory bowel disease pain.

Informations de copyright

© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For permissions, please e-mail: [e-mail].