Modulation of Serotoninergic Pathways for Treatment of Irritable Bowel Syndrome

Abstract

SUMMARY
The gut constitutes the main reservoir of the bodys serotonin.
The latter has effects not only on colonic motility via
activation of cholinergic or nitric oxide-dependent neurons
but also on the modulation of sensation by excitation of
intrinsic sensory neurons. The abundance of serotonin receptors
within the enteric nervous system constituted a challenge,
as the pharmacological intervention on these receptors
could be the etiological treatment of Irritable Bowel
Syndrome (IBS). 5-HT3 and 5-HT4 are the main subtypes of
serotonin receptors in the gut. Therapeutic blockade of 5-
HT3 by alosetron in women with diarrhea- predominant IBS
brought a revolution in the treatment of IBS. This drug acts
both on colonic motility and the secretory function of the
bowel but, despite the spectacular results, it had to be withdrawn
due to 49 cases of ischemic colitis. 5-HT4 agonists
have been used for the treatment of patients with constipation-
prone IBS. In large comparative trials tegaserod was
more effective than placebo although the therapeutic gain
over placebo was small. Prucalopride is a potent 5-HT4 agonist
but much concern has been raised by the report of
carcinogenicity in animals. Other serotonergic modulators
include piboserod (SB207266) and MKC 733 but no clinical
trials in humans are available. Sumatriptan, a 5-HT1B/D
agonist developed for the treatment of migraine, causes relaxation
of the gastric fundus in man, but its intranasal administration
limits its use. As abdominal pain constitutes
the main complaint of IBS patients, future efforts must concentrate
on medications acting on visceral hypersensivity. Key words: Alosetron, colonic motility ivisceral hypersensivity
ischemic colitis