Hydroxytryptamine Receptors

Many efforts to develop drugs for FBDs have been directed at 5-hydroxytryptamine (5-HT) receptors as is discussed in Chapter III/18. Most of the 5-HT present in the body is formed in the GI enterochromaffin cells, wherefrom it is released by a variety of luminal stimuli. Being a paracrine messenger, this indoleamine can activate intrinsic and extrinsic sensory nerve fibers as well as other enteric neurons through activation of multiple 5-HT receptors (1012). There is emerging evidence that the 5-HT system and the serotonin reuptake transporter (SERT) are modified in IBS and intestinal inflammation, which will alter the availability of 5-HT at 5-HT receptors (13-17). Thus, a strong association between the deletion/deletion polymorphic genotype in the SERT promotor region and the diarrhea-predominant IBS phenotype has been reported (17).

In terms of drug development, 5-HT3 and 5-HT4 receptors have been in the focus of interest, because their pharmacologic manipulation may correct both the functional disturbances in the gut and the pain associated with FBDs (12). This is particularly true for 5-HT3 receptors, which are present on vagal afferent neurons originating in the nodose ganglia, spinal afferents originating in the DRG, enteric neurons, and other cells of the gut. 5-HT-evoked excitation of extrinsic sensory neurons is primarily mediated by 5-HT3 receptors (10,12,18). Antagonism of 5-HT3 receptor-mediated stimulation of vagal afferents inhibits emesis induced by release of 5-HT from enterochromaffin cells (10), and blockade of 5-HT3 receptor-mediated activation of spinal afferents by alosetron depresses the afferent signaling of colorectal distension in the rat (19). Accordingly, alosetron has been found to reduce the discomfort and pain in female patients suffering from functional dyspepsia or diarrhea-predominant IBS to a moderate, but significant extent (12). However, the beneficial effect of alosetron is limited by its propensity to cause constipation and to increase the incidence of ischemic colitis in IBS patients (12). It remains to be seen whether other 5-HT3 receptor antagonists such as cilansetron will fare better in this respect.

The partial 5-HT4 receptor agonist tegaserod has been approved for the treatment of constipation-predominant IBS. While stimulating colonic transit, tegaserod also seems to reduce pain and other symptoms in female patients with constipation-predominant IBS (12) and to attenuate the pain evoked by rectal distension in healthy subjects (20). This antinociceptive activity of tegaserod is in line with experimental studies in which the drug has been found to inhibit the afferent signaling of colorectal distension in the rat and cat, particularly if there is inflammation in the colon (21,22). The mechanism behind this action of tegaserod is little understood, much as it is unknown whether blockade of 5-HT2B receptors (23) contributes to its therapeutic profile. Novel insights into tegaserod's mode of action may come from the finding that 5-HT can sensitize polymodal DRG neurons innervating the mouse colon, this effect being mediated by metabotropic 5-HT2 and 5-HT4 receptors and TRPV1 (24). 5-HTjB/D receptor agonists such as sumatriptan have been reported to relax the stomach, which may indirectly contribute to its discomfort-relieving effect in functional dyspepsia (12). 5-HT3 receptor antagonists likewise relax the intestine, an effect that may be a factor in their ability to reduce abdominal pain. It is also conceivable that 5-HT7 receptors participate in visceral nociception, because these receptors are present on dorsal root ganglion neurons with a putative role in nociception (25).

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