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By what mechanism does ondansetron inhibit colonic migrating motor complexes: does it require endogenous serotonin in

N J Spencer1, S J Nicholas, T C Sia

  • 1Discipline of Human Physiology, Flinders Medical Center, South Australia, Australia. nicholas.spencer@flinders.edu.au

Neurogastroenterology and Motility
|April 19, 2013
PubMed
Abstract

Insights

Ondansetron reduces colonic transit, but its mechanism is unclear. This study found that serotonin depletion did not affect colonic motor complexes, suggesting ondansetron

Area of Science:

  • Gastroenterology
  • Neurogastroenterology
  • Pharmacology

Background:

  • 5-HT3 antagonists like ondansetron (Zofran) treat chronic diarrhea and IBS-D by retarding colonic transit.
  • The precise mechanism by which ondansetron reduces colonic transit, potentially via colonic migrating motor complexes (CMMCs), remains to be elucidated.
  • Investigating the role of endogenous serotonin (5-HT) in CMMCs and ondansetron's efficacy is crucial for understanding its therapeutic action.

Purpose of the Study:

  • To determine if acute depletion of 5-HT from enteric neurons inhibits spontaneous CMMCs.
  • To assess if ondansetron's effectiveness in reducing CMMC frequency is altered in a 5-HT-depleted state.

Main Methods:

  • Mice were treated with reserpine to deplete neuronal 5-HT 24 hours before euthanasia.
  • Mechanical recordings of spontaneous CMMCs were performed on isolated whole mouse colons.
  • Immunohistochemistry was used to confirm 5-HT depletion in enteric nerves.

Main Results:

  • Reserpine effectively depleted all detectable 5-HT from enteric nerves.
  • 5-HT depletion did not alter the frequency or amplitude of spontaneous CMMCs in colons lacking mucosa and submucosal plexus.
  • Ondansetron equally or more effectively inhibited CMMC frequency in 5-HT-depleted preparations compared to controls.

Conclusions:

  • Endogenous 5-HT within enteric neurons or mucosa is not essential for the generation or propagation of CMMCs.
  • Ondansetron's primary mechanism for inhibiting CMMC frequency is not mediated by the mucosa, submucosal plexus, or 5-HT in myenteric neurons.
  • These findings suggest a non-serotonergic pathway or direct action of ondansetron on the myenteric neurons' motor function.

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