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6. TRPV1 receptors on unmyelinated C-fibres mediate colitis-induced sensitization of pelvic afferent nerve fibres in rats

Author

De Schepper, H U, De Winter, B Y, Van Nassauw, L, Timmermans, J-P, Herman, A G, Pelckmans, P A, and De Man, J G

Subjects
Neurons, Mice, Integrative, Animals, Humans, Pain, TRPV Cation Channels, Colitis
Abstract

Patients with inflammatory bowel disease often suffer from gastrointestinal motility and sensitivity disorders. The aim of the current study was to investigate the role of transient receptor potential of the vanilloid type 1 (TRPV1) receptors in the pathophysiology of colitis-induced pelvic afferent nerve sensitization. Trinitrobenzene sulphate (TNBS) colitis (7.5 mg, 30% ethanol) was induced in Wistar rats 72 h prior to the experiment. Single-fibre recordings were made from pelvic nerve afferents in the decentralized S1 dorsal root. Fibres responding to colorectal distension (CRD) were identified in controls and rats with TNBS colitis. The effect of the TRPV1 antagonist N-(4-tertiarybutylphenyl)-4-(3-chlorophyridin-2-yl)tetrahydropyrazine-1(2H)carboxamide (BCTC; 0.25–5 mg kg−1) or its vehicle (hydroxypropyl-β-cyclodextrin) was tested on the afferent response to repetitive distensions (60 mmHg). Immunocytochemical staining of TRPV1 and NF200, a marker for A-fibre neurons, was performed in the dorsal root ganglia L6–S1. TNBS colitis significantly increased the response to colorectal distension of pelvic afferent C-fibres. BCTC did not significantly affect the C-fibre response in controls, but normalized the sensitized response in rats with colitis. TNBS colitis increased the spontaneous activity of C-fibres, an effect which was insensitive to administration of BCTC. TNBS colitis had no effect on Aδ-fibres, nor was their activity modulated by BCTC. TNBS colitis caused an immunocytochemical up-regulation of TRPV1 receptors in the cell bodies of pelvic afferent NF200 negative neurons. TRPV1 signalling mediates the colitis-induced sensitization of pelvic afferent C-fibres to CRD, while Aδ-fibres are neither sensitized by colitis nor affected by TRPV1 inhibition.

Published
2008

10. TRPV1 receptor signaling mediates afferent nerve sensitization during colitis-induced motility disorders in rats.

Author

De Schepper HU, De Man JG, Ruyssers NE, Deiteren A, Van Nassauw L, Timmermans JP, Martinet W, Herman AG, Pelckmans PA, and De Winter BY

Subjects
Animals, Calcitonin Gene-Related Peptide pharmacology, Calcitonin Gene-Related Peptide Receptor Antagonists, Capsaicin analogs & derivatives, Capsaicin pharmacology, Colitis chemically induced, Colitis complications, Colitis metabolism, Disease Models, Animal, Dose-Response Relationship, Drug, Ganglia, Spinal drug effects, Ganglia, Spinal physiopathology, Gastric Emptying, Gastroparesis metabolism, Gastroparesis physiopathology, Intestinal Mucosa metabolism, Intestines drug effects, Intestines physiopathology, Male, Muscle Relaxation, Neurons, Afferent drug effects, Peptide Fragments pharmacology, Pyrazines pharmacology, Pyridines pharmacology, RNA, Messenger metabolism, Rats, Rats, Wistar, Receptors, Calcitonin Gene-Related Peptide metabolism, TRPV Cation Channels antagonists & inhibitors, TRPV Cation Channels genetics, Time Factors, Trinitrobenzenesulfonic Acid, Colitis physiopathology, Ganglia, Spinal metabolism, Gastrointestinal Motility drug effects, Gastroparesis etiology, Intestines innervation, Neurons, Afferent metabolism, Signal Transduction drug effects, TRPV Cation Channels metabolism
Abstract

Rats with experimental colitis suffer from impaired gastric emptying (GE). We previously showed that this phenomenon involves afferent neurons within the pelvic nerve. In this study, we aimed to identify the mediators involved in this afferent hyperactivation. Colitis was induced by trinitrobenzene sulfate (TNBS) instillation. We determined GE, distal front, and geometric center (GC) of intestinal transit 30 min after intragastric administration of a semiliquid Evans blue solution. We evaluated the effects of the transient receptor potential vanilloid type 1 (TRPV1) antagonists capsazepine (5-10 mg/kg) and N-(4-tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropyrazine-1(2H)carboxamide (BCTC; 1-10 mg/kg) and the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP-(8-37) (150 microg/kg). To determine TRPV1 receptor antagonist sensitivity, we examined their effect on capsaicin-induced relaxations of isolated gastric fundus muscle strips. Immunocytochemical staining of TRPV1 and RT-PCR analysis of TRPV1 mRNA were performed in dorsal root ganglion (DRG) L6-S1. TNBS-induced colitis reduced GE but had no effect on intestinal motility. Capsazepine reduced GE in controls but had no effect in rats with colitis. At doses that had no effects in controls, BCTC and CGRP-(8-37) significantly improved colitis-induced gastroparesis. Capsazepine inhibited capsaicin-induced relaxations by 35% whereas BCTC completely abolished them. TNBS-induced colitis increased TRPV1-like immunoreactivity and TRPV1 mRNA content in pelvic afferent neuronal cell bodies in DRG L6-S1. In conclusion, distal colitis in rats impairs GE via sensitized pelvic afferent neurons. We provided pharmacological, immunocytochemical, and molecular biological evidence that this sensitization is mediated by TRPV1 receptors and involves CGRP release.

Published
2008
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