REGULATION OF COLONIC MOTOR FUNCTION VIA ACTIVATION OF LUMINAL 5-HT4 RECEPTORS

Abstract

Functional gastrointestinal (GI) disorders including constipation and Irritable Bowel Syndrome (IBS) constitute the most widespread digestive disorders that could involve GI dysmotility and altered serotonin (5-HT) signaling. Current treatments include oral intake of prokinetic drugs such as serotonin sub-type 4 receptor (5-HT4) agonists that activate 5- HT4 receptors located on nerves in the gut wall. However, these receptors are also found on the luminal side of enterochromaffin cells in the colonic epithelium where more than 90% of the body’s 5-HT is synthesized. Therefore, activation of luminal 5-HT4 receptors by using a delivery system that releases the drug inside the colonic lumen without it being first absorbed in the upper GI tract, can result in the release of 5-HT and increase in colonic motility. This could significantly minimize the adverse side effects associated with systemic absorption of such drugs. In this study, first the rabbit animal model was used to test the effects of prucalopride after administration inside the colon (ex vivo). Results showed significant increase in propulsive motor patterns and their properties such as pressure and force. Such potent prokinetic effects occurred even in the presence of simulated fecal impaction, an acute complication of chronic constipation. Using highresolution colonic manometry (HRCM), all aspects of propulsive motility including the colo-anal reflex and simultaneous pressure waves (SPW) were studied in vivo in healthy volunteers; then, the effects of intraluminal prucalopride was evaluated with HRCM in a human case study. Similar to the animal model, marked increase in propulsive motor activity was observed. This project shows the SPW and the colo-anal reflex have potential diagnostic values in patients with colonic dysmotility or abdominal bloating and prucalopride incorporated in colon-specific drug delivery systems has the potential to become the preferred prokinetic for the treatment of constipation. It also encourages further research into the role of luminal 5-HT in generating normal colonic motor function.