ABSTRACT
Title
5-HT receptors and control of intestinal motility: expression and hierarchic role
Authors
B. Balestra1, R. Vicini1, O. Pastoris1, M. Costa2, M. Cervio1, R. De Giorgio3, M. Tonini1†
1Dept. of Legal Medicine, Forensic Sciences and Pharmaco-Toxicology, University of Pavia
2Dept. of Physiology, School of Medicine, Flinders University, Adelaide, Australia
3Dept. of Clinical Medicine, St. Orsola-Malpighi Hospital, University of Bologna
1Dept. of Legal Medicine, Forensic Sciences and Pharmaco-Toxicology, University of Pavia
2Dept. of Physiology, School of Medicine, Flinders University, Adelaide, Australia
3Dept. of Clinical Medicine, St. Orsola-Malpighi Hospital, University of Bologna
Abstract
Despite serotonin (5-hydoxytryptamine, 5-HT) exerts several functions in the Central Nervous System, its main source in the body are enterochromaffin cells (EC) of the intestinal mucosa. EC cells when stimulated by mechanical/chemical stimuli release 5-HT in the lumen. Released 5-HT participate to the regulation of intestinal motility by activating at least five receptor types, 5-HT1,2,3,4,7.
To determine the presence and localization on myenteric neurons of 5-HT3, 5-HT4 and 5-HT7 receptors we used immunohystochemistry and confocal microscopy with cultured myenteric neurons and whole mount preparations of guinea pig colon. We further investigated the relative expression of 5-HT receptors by quantitative real time RT-PCR, and defined their hierachic role in the activation and propagation of peristaltic reflex in isolated colonic segments by using selective antagonists.
5-HT receptors immunoreactivity is present on colonic ascending and descending neuronal pathways. PCR products corresponding to 5-HT3, 5-HT4 and 5-HT7 mRNAs were all present in the distal colon and real time RT-PCR showed differences in the 5-HT3, 5-HT4 and 5-HT7 receptors expression. The 5-HT3 and 5-HT7 receptor mRNAs were found in comparable amounts, but lower in density compared to the 5-HT4 mRNA. In functional studies, peristaltic activity was reduced by approximately 65%, 85% and 40% by 5-HT3, 5-HT4 and 5-HT7 receptor blockade, respectively. The administration of the antagonists given in pairs reduced persistaltic activity by approximately 16% (5-HT3+5-HT4), 70% (5-HT4+5-HT7), 87% (5-HT4+5-HT7), whereas the simultaneous administration of the three antagonists invariably blocked peristaltic activity.
5-HT plays a key role in the modulation of peristalsis since simultaneous blockade of the three receptors suppresses peristaltic activity. Among receptor subtypes, 5-HT4 receptors seem to be the most functionally important for peristalsis, followed by 5-HT3 and5-HT7 receptors.
To determine the presence and localization on myenteric neurons of 5-HT3, 5-HT4 and 5-HT7 receptors we used immunohystochemistry and confocal microscopy with cultured myenteric neurons and whole mount preparations of guinea pig colon. We further investigated the relative expression of 5-HT receptors by quantitative real time RT-PCR, and defined their hierachic role in the activation and propagation of peristaltic reflex in isolated colonic segments by using selective antagonists.
5-HT receptors immunoreactivity is present on colonic ascending and descending neuronal pathways. PCR products corresponding to 5-HT3, 5-HT4 and 5-HT7 mRNAs were all present in the distal colon and real time RT-PCR showed differences in the 5-HT3, 5-HT4 and 5-HT7 receptors expression. The 5-HT3 and 5-HT7 receptor mRNAs were found in comparable amounts, but lower in density compared to the 5-HT4 mRNA. In functional studies, peristaltic activity was reduced by approximately 65%, 85% and 40% by 5-HT3, 5-HT4 and 5-HT7 receptor blockade, respectively. The administration of the antagonists given in pairs reduced persistaltic activity by approximately 16% (5-HT3+5-HT4), 70% (5-HT4+5-HT7), 87% (5-HT4+5-HT7), whereas the simultaneous administration of the three antagonists invariably blocked peristaltic activity.
5-HT plays a key role in the modulation of peristalsis since simultaneous blockade of the three receptors suppresses peristaltic activity. Among receptor subtypes, 5-HT4 receptors seem to be the most functionally important for peristalsis, followed by 5-HT3 and5-HT7 receptors.