The Serotonin Signaling System: From Basic Understanding To Drug Development for Functional GI Disorders

Serotonin (5-HT) has been recognized for decades as an important signalling molecule in the gut, but it is still revealing its secrets. Novel gastrointestinal functions of 5-HT continue to be discovered, as well as distant actions of gut-derived 5-HT, and we are learning how 5-HT signalling is altered in gastrointestinal disorders. Conventional functions of 5-HT involving intrinsic reflexes include stimulation of propulsive and segmentation motility patterns, epithelial secretion and vasodilation. Activation of extrinsic vagal and spinal afferent fibres results in slowed gastric emptying, pancreatic secretion, satiation, pain and discomfort, as well as nausea and vomiting. Within the gut, 5-HT also exerts nonconventional actions such as promoting inflammation and serving as a trophic factor to promote the development and maintenance of neurons and interstitial cells of Cajal. Platelet 5-HT, originating in the gut, promotes haemostasis, influences bone development and serves many other functions. 5-HT3 receptor antagonists and 5-HT4 receptor agonists have been used to treat functional disorders with diarrhoea or constipation, respectively, and the synthetic enzyme tryptophan hydroxylase has also been targeted. Emerging evidence suggests that exploiting epithelial targets with nonabsorbable serotonergic agents could provide safe and effective therapies. We provide an overview of these serotonergic actions and treatment strategies.

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Serotonin signalling in the gut—functions, dysfunctions and therapeutic targets

the Enteric nervous system , the Enteric nervous system , کتابخانه دیجیتال جندی شاپور اهواز

The Enteric Nervous System

Purpose of reviewAlthough the gut contains most of the body's 5-hydroxytryptamine (5-HT), many of its most important functions have recently been discovered. This review summarizes and directs attention to this new burst of knowledge.Recent findingsEnteroendocrine cells have classically been regarde

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5-Hydroxytryptamine (serotonin) in the gastrointestinal tract.

1. Intracellular recordings have been made from neurones lying in the myenteric plexus of guinea-pig duodenum; some aspects of their membrane properties have been studied by passing current through the intracellular electrode while recording changes in membrane potential.2. The current-voltage relationship was linear for small changes in membrane potential, input resistances ranging from 125 to 250 MOmega. Larger hyperpolarizing currents (causing changes of 20-40 mV) caused the input resistance to fall.3. Depolarizing currents of 1 to 10 x 10(-10) A initiated action potentials with amplitudes of up to 95 mV.4. Two types of cell were distinguished when an action potential was initiated. In one group the action potential and undershoot had a form similar to that recorded from other mammalian ganglia. In the second group an action potential was followed by both an undershoot and a prolonged afterhyperpolarization which was associated with a decrease in cell resistance.5. The two groups of cells were further distinguished by their responses to transmural stimulation. Only those cells which did not show an afterhyperpolarization could be shown to receive a synaptic input.6. The mechanism by which each cell type generates an action potential was different. The action potentials recorded from cells which had a detectable synaptic input were abolished by tetrodotoxin. In contrast, those recorded from the other type of cells persisted in the presence of tetrodotoxin. Preliminary experiments suggest that during an action potential these cells become permeable to both sodium and calcium ions.7. Abolition of the calcium component of the action potential in cells which generated an afterhyperpolarization abolished this latter potential.8. The role of these two groups of cells is discussed.

Two types of neurones in the myenteric plexus of duodenum in the guinea-pig.

The effect of intraluminal application of 5-hydroxytryptamine and 5-hydroxytryptophan on peristalsis; the local production of 5-HT and its release in relation to intraluminal pressure and propulsive activity.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/expphysiol.1958.sp001305

R. C. Y. Lin

Papers

The effect of intraluminal application of 5-hydroxytryptamine and 5-hydroxytryptophan on peristalsis; the local production of 5-HT and its release in relation to intraluminal pressure and propulsive activity.

An investigation of the peristaltic reflex in relation to anatomical observations