The 5-HT 4 partial agonist tegaserod is effective in the treatment of chronic constipation and constipation predominant irritable bowel syndrome. 5-HT 4 receptors are located on presynaptic terminals in the enteric nervous system. Stimulation of 5-HT 4 receptors enhances the release of acetylcholine and calcitonin gene related peptide from stimulated nerve terminals. This action strengthens neurotransmission in prokinetic pathways, enhancing gastrointestinal motility. The knockout of 5-HT 4 receptors in mice not only slows gastrointestinal activity but also, after 1 month of age, increases the age-related loss of enteric neurons and decreases the size of neurons that survive. 5-HT 4 receptor agonists, tegaserod and RS67506, increase numbers of enteric neurons developing from precursor cells and/or surviving in culture; they also increase neurite outgrowth and decrease apoptosis. The 5-HT 4 receptor antagonist, GR113808, blocks all of these effects, which are thus specific and 5-HT 4 -mediated. 5-HT 4 receptor agonists, therefore, are neuroprotective and neurotrophic for enteric neurons. Because the age-related decline in numbers of enteric neurons may contribute to the dysmotilities of the elderly, the possibility that the neuroprotective actions of 5-HT agonists can be utilized to prevent the occurrence or worsening of these conditions should be investigated. Keywords5-HT 4 receptors; constipation; enteric nervous system; gastrointestinal motility; lubiprostone; tegaserod Enteric Nervous System Development is Incomplete at BirthAlthough the bowel and the enteric nervous system (ENS) of a newborn mammal must be functioning at the time of birth to cope with oral feeding, both the gut and the ENS enlarge as a function of postnatal growth. Enlargement of the ENS is not just a matter of the hypertrophy of existing cells. New neurons must also be generated. As a result, the ENS of a mature mammal contains a larger number of neurons than that of a newborn. 1,2 In mice, the birth of new neurons has been demonstrated to occur at least through postnatal day 21 (P21). 3 The corresponding age has not been ascertained for humans, but extrapolation on the basis of relative life span would suggest that it is ∼3 years. Very little is known about the postnatal generation of new enteric neurons; nevertheless, the postnatal gut has recently been demonstrated to contain stem cells, 4,5 which are a likely source of neurons added to the ENS during postnatal life. It is thus possible that neurons continue to be added to the ENS in adult life, but if so, this addition would have to occur at a rate that is too slow to be detected by the conventional techniques that have thus far been utilized to look for it. Neurons are Lost from the Mature Ens as a Function of AgeThe number of neurons in the bowel increases in postnatal life, reaches a peak and then stabilizes. 2 The age at which the peak number of neurons is achieved in humans is unknown. Ageing, however, is associated with a postpeak decline so that the senescent gut has fe...

Although serotonin (5-HT)1A receptors are known to be present on neural elements in both the bowel and the pancreas, the precise location of these receptors has not previously been determined. Earlier investigations have suggested that 5-HT1A receptors are synthesized in enteric, but not pancreatic ganglia, and that they mediate pre-and postjunctional inhibition. Wholemount in situ hybridization was used to identify cells that contain mRNA encoding 5-HT1A receptors, and immunocytochemistry was employed to locate receptor protein. mRNA encoding 5-HT1A receptors was found in the majority of neurons in both submucosal and myenteric plexuses. 5-HT1A immunoreactivity, however, was abundant only on the surfaces of a limited subset of nerve cell bodies and processes. 5-HT-immunoreactive axons were found in close proximity to sites of 5-HT1A immunoreactivity. Myenteric, but not submucosal calbindin-immunoreactive neurons (with Dogiel type II morphology) were surrounded by rings of 5-HT1A immunoreactivity. The cytoplasm of the cell bodies and dendrites of a small subset of Dogiel type I neurons was also intensely 5-HT1A immunoreactive. Most of the Dogiel type I 5-HT1A-immunoreactive myenteric neurons, and some of the type II neurons that were ringed by 5-HT1A immunoreactivity became doubly labeled following injections of the retrograde tracer, FluoroGold (FG), into the submucosal plexus. 5-HT1A-immunoreactive neurons in distant submucosal ganglia also became labeled by retrograde transport of FG. None of the 5-HT1A-immunoreactive cells were labeled by the intraluminal administration of the beta-subunit of cholera toxin, a marker for vasoactive intestinal peptide-containing secretomotor neurons. These observations suggest that some of the myenteric 5-HT1A-immunoreactive neurons project to submucosal ganglia and that the submucosal 5-HT1A-immunoreactive cells are interneurons. In addition to neurons, a subset of 5-HT-containing enterochromaffin cells expressed 5-HT1A immunoreactivity, which was co-localized with 5-HT in secretory granules. In the pancreas, 5-HT1A immunoreactivity was observed in ganglia, acinar nerves, and glucagonimmunoreactive islet cells. Serotonergic enteropancreatic axons have been found to terminate in close proximity to each of these structures, which may thus be the targets of this innervation. The abundance of 5-HT1A receptor immunoreactivity on nerves of the gut and pancreas suggests that drugs designed to interact with these receptors may have unanticipated visceral actions.

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Although nicotinic acetylcholine receptors (nAChRs) are known to be present on neural elements in both the bowel and the pancreas, the precise location of these receptors has not previously been determined. Immunocytochemistry, by using a rat monoclonal antibody (mAb35), which recognizes alpha-bungarotoxin (alpha-Bgt)-insensitive nAChRs, and a polyclonal antibody raised against the alpha-Bgt-sensitive receptor subunit, alpha7, was used to locate receptor protein in guinea pig gut and pancreas. mAb35-receptor (mAb35-R) immunoreactivity was abundant in both enteric plexuses, enterochromaffin cells, and pancreatic ganglia. Immunostaining was associated with the cell membrane, and clusters of mAb35-R were observed on cell somas and dendrites. Receptor immunoreactivity was also observed on terminals and axons, suggesting that a subset of nAChRs is presynaptic. Internal sites of mAb35-R were observed in permeabilized ganglia. Cells expressing the receptors were closely associated with ChAT-immunoreactive nerve fibers. In addition, the majority of ChAT-positive neurons expressed both cell surface and internal stores of mAb35-R. In the bowel, clusters of mAb35-R were present on the soma and dendrites of Dogiel type I motorneurons and secretomotor neurons. Receptors were detected at the plasma membrane of calbindin-immunoreactive myenteric neurons. In contrast, calbindin-immunoreactive submucosal neurons did not express cell surface mAb35-R, supporting the idea that they are sensory neurons. A subset of enteric neurons expressed both mAb35-R and glutamate receptor (GluR1) immunoreactivity. In the pancreas, mAb35-R immunoreactivity was only observed in ganglia. Alpha7-immunoreactivity was found on both enteric cell bodies and nerve fibers. Based on these results, it appears that visceral nAChRs are composed of at least four subunits and that both pre- and postsynaptic nAChRs are present in the gut and pancreas.

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