Activation of colonic mucosal 5-HT(4) receptors accelerates propulsive motility and inhibits visceral hypersensitivity

Gastroenterology. 2012 Apr;142(4):844-854.e4. doi: 10.1053/j.gastro.2011.12.041. Epub 2012 Jan 4.


Background & aims: 5-hydroxytryptamine receptor (5-HT(4)R) agonists promote gastrointestinal motility and attenuate visceral pain, but concerns about adverse reactions have restricted their availability. We tested the hypotheses that 5-HT(4) receptors are expressed in the colonic epithelium and that 5-HT(4)R agonists can act intraluminally to increase motility and reduce visceral hypersensitivity.

Methods: Mucosal expression of the 5-HT(4)R was evaluated by reverse-transcriptase polymerase chain reaction and immunohistochemical analysis of tissues from 5-HT(4)R(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-HT(4)R compounds included cisapride, tegaserod, naronapride, SB204070, and GR113808.

Results: Mucosal 5-HT(4) receptors were present in the small and large intestines. In the distal colon, 5-HT(4) receptors were expressed by most epithelial cells, including enterochromaffin and goblet cells. Stimulation of 5-HT(4)Rs evoked mucosal 5-HT release, goblet cell degranulation, and Cl(-) secretion. Luminal administration of 5-HT(4)R agonists accelerated propulsive motility; a 5-HT(4)R antagonist blocked this effect. Bath application of 5-HT(4)R agonists did not affect motility. Oral or intracolonic administration of 5-HT(4)R agonists attenuated visceral hypersensitivity. Intracolonic administration was more potent than oral administration, and was inhibited by a 5-HT(4)R antagonist.

Conclusions: Mucosal 5-HT(4) receptor activation can mediate the prokinetic and antinociceptive actions of 5-HT(4)R agonists. Colon-targeted, intraluminal delivery of 5-HT(4)R agonists might be used to promote motility and alleviate visceral pain, while restricting systemic bioavailability and resulting adverse side effects.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Analgesics / administration & dosage
  • Analgesics / pharmacology*
  • Animals
  • Chlorides / metabolism
  • Chromosomes, Artificial, Bacterial
  • Colon / drug effects*
  • Colon / innervation
  • Colon / metabolism
  • Disease Models, Animal
  • Enterochromaffin Cells / drug effects
  • Enterochromaffin Cells / metabolism
  • Gastrointestinal Agents / administration & dosage
  • Gastrointestinal Agents / pharmacology*
  • Gastrointestinal Motility / drug effects*
  • Goblet Cells / drug effects
  • Goblet Cells / metabolism
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Guinea Pigs
  • Humans
  • Hyperalgesia / metabolism
  • Hyperalgesia / physiopathology
  • Hyperalgesia / prevention & control*
  • Immunohistochemistry
  • Intestinal Mucosa / drug effects*
  • Intestinal Mucosa / innervation
  • Intestinal Mucosa / metabolism
  • Male
  • Membrane Potentials
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Mucus / metabolism
  • Pain / metabolism
  • Pain / physiopathology
  • Pain / prevention & control*
  • Pain Threshold / drug effects
  • Pressure
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Serotonin, 5-HT4 / drug effects*
  • Receptors, Serotonin, 5-HT4 / genetics
  • Receptors, Serotonin, 5-HT4 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Serotonin / metabolism
  • Serotonin 5-HT4 Receptor Agonists / administration & dosage
  • Serotonin 5-HT4 Receptor Agonists / pharmacology*


  • Analgesics
  • Chlorides
  • Gastrointestinal Agents
  • Serotonin 5-HT4 Receptor Agonists
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • Receptors, Serotonin, 5-HT4
  • Serotonin