Proceedings of The Physiological Society
University of Oxford (2011) Proc Physiol Soc 23, PC178
A murine model of slow transit constipation induced by outlet obstruction.
D. J. Heredia1, P. O. Bayguinov1, T. K. Smith1
1. Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, United States.
Background: The spontaneous colonic migrating motor complex (CMMC) is responsible for fecal pellet migration. Colonic elongation evokes the “occult reflex” that activates mechanosensitive descending interneurons that release nitric oxide to inhibit the neural circuitry underlying the CMMC (Heredia et al., 2010). It has been suggested that the “occult reflex” activated by colonic elongation may contribute to slow transit constipation (STC) in humans (Southwell, 2010). The aim of this study was to produce a non-pharmacological, phenotypically analogous and easily inducible model for STC. Methods: The maximal anal sphincter opening was physically reduced in anesthetized (isoflourane inhalation, 1.75%) C57 mice to 2.5 mm using a purse string suture. 4 days following suture placement, mice were either sacrificed (obstructed) or the suture removed (relieved). Following sacrifice the entire gastrointestinal tract was removed. Spontaneous fecal pellet transit and colonic motility were recorded using a CCD camera and isometric tension transducers respectively. Intracellular microelectrodes were used to record electrical activity of the circular muscle. Results: Obstructed mice compared to controls exhibited an elongated (control 49.7 ± 0.8mm; obstructed 66.3 ±1.6mm; p<0.01, n=5) impacted large bowel with no discrete fecal pellets; a reduced daily output of fecal dry matter (control 0.40 ± 0.03g and obstructed 0.13 ± 0.01g; p<0.01, n=10); slowed transit of an artificial pellet along the emptied colon (control 0.68 ± 0.07mm/s and obstructed 0.28 ± 0.13mm/s; p<0.01, n=5), and abnormal or uncoupled CMMC propagation. As the obstructed colon slowly emptied it became hyperactive, generating more frequent CMMCs. The circular muscle in the obstructed colon was further depolarized (control -61.3 ± 4.1mV and obstructed -49.8 ± 6.2mV; p<0.01, n=5) owing to a lack of spontaneous inhibitory junction potentials. Colonic elongation applied to the empty obstructed colon produced a pronounced “occult reflex”. In 3 out of 10 animals we observed a jejunal volvulus (ischemic twisted section of bowel). In relieved animals (7 days post suture removal) there was no significant difference in colonic size, fecal output, fecal transit speed, CMMC propagation, membrane potential, and spontaneous inhibitory junction potential occurrence from controls. Conclusions: These results illustrate parallels between surgically obstructed mice and outlet obstruction induced STC in humans: slowed fecal pellet transit, decreased fecal output and elongated large bowels. Interestingly, outlet obstruction appears to produce a hyper-excitable colon including an absence of tonic inhibition of the circular muscle. This hyper-excitability appears to be suppressed by the "occult reflex" triggered by colonic elongation.
Where applicable, experiments conform with Society ethical requirements