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Activation of Colonic Mucosal 5-HT4 Receptors Accelerates Propulsive Motility and Inhibits Visceral Hypersensitivity
Open accessAbstract
BACKGROUND & AIMS 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.
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Metadata
- Authors
- Hoffman, J. M., Tyler, K., MacEachern, S. J., Balemba, O. B., Johnson, A. C., Brooks, E. M., Zhao, H., Swain, G. M., Moses, P. L., Galligan, J. J., Sharkey, K. A., Greenwood–Van Meerveld, B., & Mawe, G. M.
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2012-04
- Volume
- 142
- Issue
- 4
- Pages
- 844-854.e4
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W1972348334
- Cited by
- 266
- References
- 0
- FWCI
- 14.88
- Type
- journal article
- Language
- en
- Open access
- bronze
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