title: By what mechanism does ondansetron inhibit colonic migrating motor complexes: does it require endogenous serotonin in the gut wall?
abstract: BACKGROUND
  5-HT3 antagonists, such as ondansetron (Zofran), retard colonic transit and provide effective relief of symptoms of chronic diarrhea and diarrhea-predominant irritable bowel syndrome (IBS), but the mechanism by which ondansetron retards transit is unclear. What is clear is that the frequency of colonic migrating motor complexes (CMMCs) is reduced by ondansetron, which could account for reduced transit. Our aim was to determine whether an acute depletion of 5-HT from enteric neurons would inhibit spontaneous CMMCs; and determine whether the sensitivity of ondansetron to reduce CMMC frequency would change in a 5-HT-depleted preparation.
  
  
  METHODS
  Mice were injected with reserpine, 24 h prior to euthanasia to deplete neuronally synthesized 5-HT. Mechanical recordings were made from proximal and mid-distal regions of isolated whole mouse colon. Immunohistochemical staining for 5-HT was used to detect neuronal 5-HT.
  
  
  RESULTS
  Reserpine depleted all detectable 5-HT from enteric nerves. In whole colons, with mucosa and submucosal plexus removed, the frequency and amplitude of spontaneous CMMCs was not different between groups treated with or without reserpine. Surprisingly, in mucosa and submucosal plexus-free preparations, ondansetron was equally or significantly more effective at inhibiting CMMC frequency compared with control preparations (containing 5-HT). Reserpine pretreatment had no effect on the sensitivity of ondansetron to inhibit CMMCs.
  
  
  CONCLUSIONS
  Endogenous 5-HT in enteric neurons (or the mucosa) is not required for the spontaneous generation or propagation of CMMCs. Furthermore, the primary mechanism by which ondansetron inhibits CMMC frequency is not mediated via the mucosa, submucosal plexus or 5-HT in myenteric neurons.
authors.affiliation: Discipline of Human Physiology, Flinders Medical Center, South Australia, Australia. nicholas.spencer@flinders.edu.au
authors.forename: N J
authors.initials: NJ
authors.lastname: Spencer
authors.forename: S J
authors.initials: SJ
authors.lastname: Nicholas
authors.forename: T C
authors.initials: TC
authors.lastname: Sia
authors.forename: V
authors.initials: V
authors.lastname: Staikopoulos
authors.forename: M
authors.initials: M
authors.lastname: Kyloh
authors.forename: E A
authors.initials: EA
authors.lastname: Beckett
mesh_terms: D000818:Animals; D003106:Colon / Q000187:drug effects* / Q000378:metabolism; D006168:Guinea Pigs; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009197:Myenteric Plexus / Q000187:drug effects / Q000378:metabolism; D016065:Myoelectric Complex, Migrating / Q000187:drug effects* / Q000502:physiology; D017294:Ondansetron / Q000494:pharmacology*; D012701:Serotonin / Q000172:deficiency; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013368:Submucous Plexus / Q000187:drug effects* / Q000378:metabolism
chemical_list: D012702:Serotonin Antagonists; D012701:Serotonin; D017294:Ondansetron