H. U. De Schepper

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

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.

Review article : gastrointestinal sensory and motor disturbances in inflammatory bowel disease -clinical relevance and pathophysiological mechanisms

Background  It is well known that inflammation has a profound impact on the neuromuscular apparatus of the gastrointestinal tract during the inflammatory insult and in periods of remission, at the site of inflammation and at distance from this site. The importance of this interaction is illustrated by the higher prevalence of functional gut disorders in patients with inflammatory bowel disease.

Acute distal colitis impairs gastric emptying in rats via an extrinsic neuronal reflex pathway involving the pelvic nerve

Background and aims: Patients with inflammatory bowel disease often present with abnormal gut motility away from the inflammatory site. We studied remote motility disturbances and their pathophysiology in a rat model of colitis. Methods: Colitis was induced 72 h prior to experiments using trinitrobenzene sulphate (TNBS) instillation. Inflammation was verified using histology and myeloperoxidase (MPO) measurements. To assess gut motility, we determined gastric emptying, distal front and geometric centre (GC) of intestinal transit 30 min after intragastric administration of a semiliquid Evans blue solution. The effects of hexamethonium (20 mg/kg), capsaicin (125 mg/kg) and pelvic nerve section on colitis induced motility changes were evaluated. c-Fos expression was studied in the pelvic nerve dorsal root ganglion (DRG) S1. Results: Colitis reduced gastric emptying from 38.4 (3.6)% in controls to 22.7 (4.4)% in TNBS treated rats in the absence of local gastric inflammation. Colitis had no effect on the distal front or on the geometric centre of small intestinal transit. Hexamethonium reduced gastric emptying in controls to 26.3 (4.1)% but restored it to 35.8 (4.4)% in TNBS treated rats. Capsaicin significantly impaired gastric emptying in controls from 33.1 (5.2)% to 9.5 (3.3)% while this effect was less pronounced in TNBS treated rats (from 19.2 (2.3)% to 11.5 (3.8)%; NS). In TNBS treated rats, pelvic nerve section completely restored gastric emptying from 19.8 (5.3)% to 52.5 (6.3)% without any effect on gastric emptying in control rats. TNBS colitis induced de novo c-Fos expression in the DRG S1. Conclusions: Experimental colitis in rats delays gastric emptying via a neuronal pathway involving pelvic afferent nerve hyperactivity.

Functional study on TRPV1-mediated signalling in the mouse small intestine: involvement of tachykinin receptors.

Abstract  Afferent nerves in the gut not only signal to the central nervous system but also provide a local efferent‐like effect. This effect can modulate intestinal motility and secretion and is postulated to involve the transient receptor potential of the vanilloid type 1 (TRPV1). By using selective TRPV1 agonist and antagonists, we studied the efferent‐like effect of afferent nerves in the isolated mouse jejunum. Mouse jejunal muscle strips were mounted in organ baths for isometric tension recordings. Jejunal strips contracted to the TRPV1 agonist capsaicin. Contractions to capsaicin showed rapid tachyphylaxis and were insensitive to tetrodotoxin, hexamethonium, atropine or l‐nitroarginine. Capsaicin did not affect contractions to electrical stimulation of enteric motor nerves and carbachol. Tachykinin NK1, NK2 and NK3 receptor blockade by RP67580, nepadutant plus SR‐142801 reduced contractions to capsaicin to a similar degree as contractions to substance P. The effect of the TRPV1 antagonists capsazepine, SB‐366791, iodo‐resiniferatoxin (iodo‐RTX) and N‐(4‐tertiarybutylphenyl)‐4‐(3‐cholorphyridin‐2‐yl)tetrahydropyrazine‐1(2H)‐carbox‐amide (BCTC) was studied. Capsazepine inhibited contractions not only to capsaicin but also those to carbachol. SB‐366791 reduced contractions both to capsaicin and carbachol. Iodo‐RTX partially inhibited the contractions to capsaicin without affecting contractions to carbachol. BCTC concentration‐dependently inhibited and at the highest concentration used, abolished the contractions to capsaicin without affecting those to carbachol. From these results, we conclude that activation of TRPV1 in the mouse intestine induces a contraction that is mediated by tachykinins most likely released from afferent nerves. The TRPV1‐mediated contraction does not involve activation of intrinsic enteric motor nerves. Of the TRPV1 antagonists tested, BCTC combined strong TRPV1 antagonism with TRPV1 selectivity.

Distal esophageal spasm and the Chicago classification: is timing everything?

According to the Chicago classification of esophageal motility disorders, distal esophageal spasm (DES) is defined as premature esophageal contractions (distal latency [DL] <4.5 s) for ≥20% of swallows, in the presence of a normal mean integral relaxation pressure (IRP). However, some patients with symptoms of DES have rapid contractions with a normal DL. The aim of this study was to characterize these patients and compare their clinical characteristics to those of patients classified as DES.

Impact of spatial resolution on results of esophageal high-resolution manometry

The Chicago classification for esophageal motility disorders was designed for a 36‐channel manometry system with sensors spaced at 1 cm. However, many motility laboratories outside the USA use catheters with a lower resolution in the segments outside the esophagogastric junction. Our aim was to investigate the effect of spatial resolution on the Chicago metrics and diagnosis.

Differential role of tachykinin NK3 receptors on cholinergic excitatory neurotransmission in the mouse stomach and small intestine

Tachykinin NK3 receptors are widely expressed in the mouse gastrointestinal tract but their functional role in enteric neuromuscular transmission remains unstudied in this species. We investigated the involvement of NK3 receptors in cholinergic neurotransmission in the mouse stomach and small intestine.

Mechanisms contributing to visceral hypersensitivity: focus on splanchnic afferent nerve signaling.

Visceral hypersensitivity is a main characteristic of functional bowel disorders and is mediated by both peripheral and central factors. We investigated whether enhanced splanchnic afferent signaling in vitro is associated with visceral hypersensitivity in vivo in an acute and postinflammatory rat model of colitis.