Luminal Cholera Toxin Alters Motility in Isolated Guinea-Pig Jejunum via a Pathway Independent of 5-HT3 Receptors

Candice Fung,Joel C Bornstein,Melina Ellis

doi:10.3389/fnins.2010.00162

Abstract

Cholera toxin (CT) is well established to produce diarrhea by producing hyperactivity of the enteric neural circuits that regulate water and electrolyte secretion. Its effects on intestinal motor patterns are less well understood. We examined the effects of luminal CT on motor activity of guinea-pig jejunum in vitro. Segments of jejunum were cannulated at either end and mounted horizontally. Their contractile activity was video-imaged and the recordings were used to construct spatiotemporal maps of contractile activity with CT (1.25 or 12.5 μg/ml) in the lumen. Both concentrations of CT induced propulsive motor activity in jejunal segments. The effect of 1.25 μg/ml CT was markedly enhanced by co-incubation with granisetron (5-HT3 antagonist, 1 μM), which prevents the hypersecretion induced by CT. The increased propulsive activity was not accompanied by increased segmentation and occurred very early after exposure to CT in the presence of granisetron. Luminal CT also reduced the pressure threshold for saline distension evoked propulsive reflexes, an effect resistant to granisetron. In contrast, CT prevented the induction of segmenting contractions by luminal decanoic acid, so its effects on propulsive and segmenting contractile activity are distinctly different. Thus, in addition to producing hypersecretion, CT excites propulsive motor activity with an entirely different time course and pharmacology, but inhibits nutrient-induced segmentation. This suggests that CT excites more than one enteric neural circuit and that propulsive and segmenting motor patterns are differentially regulated.

Highlights

Cholera toxin (CT) exerts much of its pathogenic effects via the enteric nervous system, acting to produce massively increased firing of secretomotor neurons and hypersecretion leading to severe diarrhea
Cholera toxin-induced secretion is blocked by 5-HT3 receptor antagonists in vivo (Buchheit, 1989; Kordasti et al, 2006) and a 5-HT3 antagonist granisetron (1 μM) prevents CT-induced hyperexcitability of submucosal secretomotor neurons in guinea-pig jejunum in vitro (Gwynne et al, 2009)
Granisetron reveals an initial increase in contractile activity, which declines to the ongoing elevated level of activity seen during continued exposure to CT

Summary

Introduction

Cholera toxin (CT) exerts much of its pathogenic effects via the enteric nervous system, acting to produce massively increased firing of secretomotor neurons and hypersecretion leading to severe diarrhea (for reviews see Lundgren and Jodal, 1997; Farthing, 2000, 2002). CT produces neural activity during the incubation period, perhaps even before the enhanced secretion. Most studies to date have been performed in vivo and lacked the spatial resolution needed to fully characterize organized motility patterns and their relationships. Kordasti et al (2006) reported that distension of rat upper small intestine after 2 h of luminal CT incubation in vivo induced clusters of contractions that were absent in control conditions. This study lacked spatial resolution as contractions were identified as pressure changes recorded at a single point, so whether the contractions were propagating (propulsive) or stationary (segmenting) could not be determined. While CT alters motility patterns, these patterns have not been characterized in relation to normal intestinal motility

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Conclusion