TRPV1 receptor signaling mediates afferent nerve sensitization during colitis-induced motility disorders in rats.
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.
De Schepper
H U
HU
Laboratory of Gastroenterology, Faculty of Medicine, Univ. of Antwerp, Universiteitsplein 1, 2610 Antwerp (Belgium benedicte.dewinter@ua.ac.be).
De Man
J G
JG
Ruyssers
N E
NE
Deiteren
A
A
Van Nassauw
L
L
Timmermans
J-P
JP
Martinet
W
W
Herman
A G
AG
Pelckmans
P A
PA
De Winter
B Y
BY
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D003092:Colitis / Q000139:chemically induced / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D005746:Gastric Emptying; D005769:Gastrointestinal Motility / Q000187:drug effects; D018589:Gastroparesis / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000294:innervation* / Q000503:physiopathology; D008297:Male; D009126:Muscle Relaxation; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014302:Trinitrobenzenesulfonic Acid
D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; C475772:N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide; D010446:Peptide Fragments; D011719:Pyrazines; D011725:Pyridines; D012333:RNA, Messenger; D018015:Receptors, Calcitonin Gene-Related Peptide; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C058636:calcitonin gene-related peptide (8-37); D014302:Trinitrobenzenesulfonic Acid; D015740:Calcitonin Gene-Related Peptide; C071423:capsazepine; D002211:Capsaicin