5-HT released by mucosal stimuli initiates peristalsis by activating 5-HT4/5-HT1p receptors on sensory CGRP neurons

Grider, John R.; Kuemmerle, John F.; Jin, Ji‐Guang

doi:10.1152/ajpgi.1996.270.5.g778

Cited by 145 publications

(218 citation statements)

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“…In fact, 5-HT3 and 5-HT4 receptors are crucial in the regulation of intestinal motility and the peripheral peristaltic reflex. This action is performed by the release of serotonin by enterochromaffin cells to intrinsic and extrinsic efferent neurons [20,23,[29][30][31] (Fig. 2).…”

Section: Serotonin Synthesis and Physiologymentioning

confidence: 99%

Inhibition of Peripheral Synthesis of Serotonin as a New Target in Neuroendocrine Tumors

et al. 2016

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The carcinoid syndrome represents a set of signs and symptoms associated with neuroendocrine tumors (NETs) that occur primarily when metastases are developed in the liver, resulting in the worsening of quality of life. Serotonin plays a central role in the physiology of carcinoid syndrome by promoting intestinal motility. Somatostatin analogs (SSAs) have widely demonstrated their efficacy as symptomatic relievers of carcinoid syndrome, but this control is ephemeral, being reduced by approximately 50% within the first year. The exact mechanisms of resistance to SSAs are not fully understood, but it is believed that serotonin might be involved. Patients with carcinoid syndrome present with a significant increase in serotonin plasma levels and, consequently, in the soluble urinary metabolite 5‐hydroxyindole acetic acid. Telotristat etiprate is a potent inhibitor of tryptophan hydroxylase, a rate‐limiting enzyme in the synthesis of serotonin, that has demonstrated in the phase III TELESTAR clinical trial a significant improvement in the control of bowel movements in patients with NETs who have carcinoid syndrome and who have progressed to an SSA. Based on these results, telotristat etiprate has emerged as a potential new option in the treatment algorithm of symptomatic control of functioning NETs. However, some issues need to be clarified, such as the safety profile of the drug outside clinical trials, the benefit in quality of life, and the possible impact on tumor growth, as well as its role within sequencing or combination treatment strategies with pre‐existing drugs effective in NET treatment. Implications for Practice: This article reviews the literature about carcinoid syndrome, which affects patients diagnosed with neuroendocrine tumors. Few articles have been published about this syndrome and its pathophysiology. Somatostatin analogs provide symptomatic relief; however, patients may become refractory to this strategy, usually within the first year of treatment. In this context, as an agent with an innovative mechanism of action, telotristat etiprate has demonstrated activity in a phase III trial, and findings may offer a path to an improve quality of life and prolonged survival for certain patients.

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Section: Serotonin Synthesis and Physiologymentioning

confidence: 99%

Inhibition of Peripheral Synthesis of Serotonin as a New Target in Neuroendocrine Tumors

et al. 2016

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“…5-HT might also be secreted by endocrine cells and act as a hormone or through activation of local neural pathways. Numerous studies revealed that 5-HT was released in response to pressure, mucosal stimuli from the intestinal mucosa and evoked peristaltic or secretory reflexes (Kirchgessner et al, 1992;Grider et al, 1996;Zhu et al, 2001;Bertrand, 2007;Patel et al, 2007).…”

Section: -Ht and Tachykinin In The Rabbit Ileummentioning

confidence: 99%

“…Numerous pharmacological studies have provided evidence that 5-HT can act on the secretion of intestinal fluid and electrolytes (Bjorck et al, 1988) and gastrointestinal motility (Grider et al, 1996;Wade et al, 1996;Bush et al, 2001). In guinea pig, morphological studies described a rich, varicose 5-HT-immunoreactive (IR) fiber network in the myenteric and submucous plexuses and reactive nerve cells with short, broad dendrites and a single long process in the myenteric plexus (Costa et al, 1982).…”

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confidence: 99%

Interactions of Serotoninergic, Cholinergic, and Tachykinin‐Containing Nerve Elements in the Rabbit Small Intestine

Denes

Wilhelm

NÉMeth

et al. 2009

The Anatomical Record

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This report presents novel results on the effects of serotonin (5-HT) on longitudinal muscle contractions in the rabbit ileum and the interactions of serotonin with some neuronal elements of the myenteric plexus. We showed previously that serotonin-triggered contractions involved two mechanisms in the rabbit ileum: neuronal excitation (via 5-HT 2 receptors in the neurons) and direct muscular stimulation (via 5-HT 4 receptors in the muscle). Here, we focus on the neuronal 5-HT 2 receptor pathway and report further pharmacological and immunocytochemical data clarifying the details of the mechanisms. We observed that antagonists for neurokinin (NK1 and NK2) receptors partially blocked the serotonin response, but NK3 receptor antagonists had no effect. Pretreatment by atropine (ATR) eliminated the NK1 receptor antagonist resistant contractions. In contrast, the NK1 antagonist did not depress the ATR-resistant contraction when ATR was added first. 5-HT 2 receptor agonist-induced contractions were partially suppressed by ATR, hexamethonium, and NK1 or NK2 receptor antagonists. In conclusion, serotonin acting through 5-HT 2 receptors could stimulate interneurons and excitatory motor neurons. Immunocytochemical staining revealed an extensive tachykinin-immunoreactive (IR) network in the myenteric plexus. Approximately 52% of all myenteric neurons were labeled. 5-HT-IR fibers could be detected around both choline acetyltransferase-and tachykinin-IR cells, suggesting functional relationships between them. Consistent with our pharmacological observations, we found that immunopositive nerve elements for 5-HT 2A receptor and double-labeled immunostaining revealed a remarkable overlap between tachykinin-IR neurons and 5-HT 2A -IR elements. Anat Rec, 292:1548Rec, 292: -1558Rec, 292: , 2009. Key words: ileum; 5-HT; tachykinins; 5-HT 2 receptors; rabbit One of the principal regulators of digestion in mammals is the enteric nervous system. Enteric neurons coordinate a variety of functions, such as the secretion of digestive enzymes, control of absorption, and the regulation of motility. Intestinal smooth muscle contractility is organized by polarized reflex pathways through both excitatory and inhibitory neurons (Goyal and Hirano, 1996;Kunze and Furness, 1999;Olsson and Holmgren,

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“…The released Ach and CGRP excite the ascending and descending interneurons, which in turn release Ach at their terminals. Presynaptic 5HT4 receptors also augment this Ach release (Grider 1996;Gershon 2004Gershon , 2005. The ascending interneurons synapse with excitatory motor neurons cephalad to the site of stimulus (bolus), which release Ach and substance P. This results in smooth muscle contraction cephalad to the bolus.…”

Section: Enteric Nervous System Serotonin and Serotonin Receptorsmentioning

confidence: 99%

“…This whole process results in propagation of the bolus in a coordinated fashion. 5HT1p receptors play a key role in the initiation of peristalsis, whereas 5HT4 receptors play a role in augmenting the release of neurotransmitters once the process is initiated by 5HT1p receptor stimulation (Grider 1996;Gershon 2004Gershon , 2005. 5HT3 receptors are found on the terminals of extrinsic afferent neurons, and are involved in the transmission of sensory stimuli to the CNS.…”

Section: Enteric Nervous System Serotonin and Serotonin Receptorsmentioning

confidence: 99%

Serotonin receptor modulators in the treatment of irritable bowel syndrome

Fayyaz

Lackner

2008

TCRM

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Abstract:The aim of this article is to review the pathophysiology and clinical role of serotonin receptor modulators used in the treatment of irritable bowel syndrome. Serotonin is an important monoamine neurotransmitter that plays a key role in the initiation of peristaltic and secretory refl exes, and in modulation of visceral sensations. Several serotonin receptor subtypes have been characterized, of which 5HT3, 5HT4, and 5HT1b are the most important for GI function. 5HT4 agonists (eg, tegaserod) potentiate peristalsis initiated by 5HT1 receptor stimulation. 5HT4 agonists are therefore useful in constipation predominant form of IBS and in chronic constipation. 5HT3 antagonists (Alosetron and Cilansetron) prevent the activation of 5HT3 receptors on extrinsic afferent neurons and can decrease the visceral pain associated with IBS. These agents also retard small intestinal and colonic transit, and are therefore useful in diarrhea-predominant IBS. Tegaserod has been demonstrated in several randomized, placebo controlled trials to relieve global IBS symptoms as well as individual symptoms of abdominal discomfort, number of bowel movements and stool consistency. Several randomized, controlled trials have shown that alosetron relieves pain, improves bowel function, and provides global symptom improvement in women with diarrhea-predominant irritable bowel syndrome. However, ischemic colitis and severe complications of constipation have been major concerns leading to voluntary withdrawal of Alosetron from the market followed by remarketing with a comprehensive risk management program.

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5-HT released by mucosal stimuli initiates peristalsis by activating 5-HT4/5-HT1p receptors on sensory CGRP neurons

Cited by 145 publications

References 0 publications

Inhibition of Peripheral Synthesis of Serotonin as a New Target in Neuroendocrine Tumors

Inhibition of Peripheral Synthesis of Serotonin as a New Target in Neuroendocrine Tumors

Interactions of Serotoninergic, Cholinergic, and Tachykinin‐Containing Nerve Elements in the Rabbit Small Intestine

Serotonin receptor modulators in the treatment of irritable bowel syndrome

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