5-hydroxytryptamine receptor (5-HT₄R) agonists promote gastrointestinal motility and attenuate visceral pain, but concerns about adverse reactions have restricted their availability. We tested the hypotheses that 5-HT₄ receptors are expressed in the colonic epithelium and that 5-HT₄R agonists can act intraluminally to increase motility and reduce visceral hypersensitivity.

Mucosal expression of the 5-HT₄R was evaluated by reverse-transcriptase polymerase chain reaction and immunohistochemical analysis of tissues from 5-HT₄R(BAC)-enhanced green fluorescent protein mice. Amperometry, histology, and short-circuit current measurements were used to study 5-HT, mucus, and Cl⁻ secretion, respectively. Propulsive motility was measured in guinea pig distal colon, and visceromotor responses were recorded in a rat model of colonic hypersensitivity. 5-HT₄R compounds included cisapride, tegaserod, naronapride, SB204070, and GR113808.

Mucosal 5-HT₄ receptors were present in the small and large intestines. In the distal colon, 5-HT₄ receptors were expressed by most epithelial cells, including enterochromaffin and goblet cells. Stimulation of 5-HT₄Rs evoked mucosal 5-HT release, goblet cell degranulation, and Cl⁻ secretion. Luminal administration of 5-HT₄R agonists accelerated propulsive motility; a 5-HT₄R antagonist blocked this effect. Bath application of 5-HT₄R agonists did not affect motility. Oral or intracolonic administration of 5-HT₄R agonists attenuated visceral hypersensitivity. Intracolonic administration was more potent than oral administration, and was inhibited by a 5-HT₄R antagonist.

Mucosal 5-HT₄ receptor activation can mediate the prokinetic and antinociceptive actions of 5-HT₄R agonists. Colon-targeted, intraluminal delivery of 5-HT₄R agonists might be used to promote motility and alleviate visceral pain, while restricting systemic bioavailability and resulting adverse side effects.