CrossTalk opposing view: 5‐HT is not necessary for peristalsis

Spencer, Nick J.; Sia, Tiong Cheng; Brookes, Simon Jonathan; Costa, Marcello; Keating, Damien J.

doi:10.1113/jp270183

Cited by 49 publications

(31 citation statements)

References 30 publications

(59 reference statements)

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“…Consistent with this view, and with studies reporting a substantial effect of 5-HT 3 antagonists only in the presence of high levels of 5-HT, either exogenously administered or endogenously released from enterochromaffin cells (for example, by mucosal pressure, distortion and/or chemical stimuli[31-33]), granisetron administration in vitro did not significantly inhibit the contractile response to EFS and showed a borderline trend to increase the contraction mediated by ACh ( P = 0.09). Interestingly, colon contractile responses to EFS were decreased in vitro by incubation with ZnPPIX alone.…”

Section: Discussionsupporting

confidence: 62%

Carbon monoxide contributes to the constipating effects of granisetron in rat colon

Nacci¹,

Fanelli²,

Potenza³

et al. 2016

WJG

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AIMTo investigate the mechanisms underlying the potential contribution of the heme oxygenase/carbon monoxide (HO/CO) pathway in the constipating effects of granisetron.METHODSFor in vivo studies, gastrointestinal motility was evaluated in male rats acutely treated with granisetron [25, 50, 75 μg/kg/subcutaneous (sc)], zinc protoporphyrin IX [ZnPPIX, 50 μg/kg/intraperitoneal (ip)] and hemin (50 μmol/L/kg/ip), alone or in combination. For in vitro studies, the contractile neurogenic response to electrical field stimulation (EFS, 3, 5, 10 Hz, 14 V, 1 ms, pulse trains lasting 10 s), as well as the contractile myogenic response to acetylcholine (ACh, 0.1-100 μmol/L) were evaluated on colon specimens incubated with granisetron (3 μmol/L, 15 min), ZnPPIX (10 μmol/L, 60 min) or CO-releasing molecule-3 (CORM-3, 100, 200, 400 μmol/L) alone or in combination. These experiments were performed under co-treatment with or without atropine (3 μmol/L, a muscarinic receptor antagonist) or NG-nitro-L-Arginine (L-NNA, 100 μmol/L, a nitric oxide synthase inhibitor).RESULTSAdministration of granisetron (50, 75 μg/kg) in vivo significantly increased the time to first defecation (P = 0.045 vs vehicle-treated rats), clearly suggesting a constipating effect of this drug. Although administration of ZnPPIX or hemin alone had no effect on this gastrointestinal motility parameter, ZnPPIX co-administered with granisetron abolished the granisetron-induced constipation. On the other hand, co-administration of hemin and granisetron did not modify the increased constipation observed under granisetron alone. When administered in vitro, granisetron alone (3 μmol/L) did not significantly modify the colon’s contractile response to either EFS or ACh. Incubation with ZnPPIX alone (10 μmol/L) significantly reduced the colon’s contractile response to EFS (P = 0.016) but had no effect on contractile response to ACh. Co-administration of ZnPPIX and atropine (3 μmol/L) abolished the ZnPPIX-mediated decrease in contractile response to EFS. Conversely, incubation with CORM-3 (400 μmol/L) alone increased both the contractile response to EFS at 10 Hz (10 Hz: 71.02 ± 19.16 vs 116.25 ± 53.70, P = 0.01) and the contractile response to ACh (100 μmol/L) (P = 0.012). Co-administration of atropine abolished the CORM-3-mediated effects on the EFS-mediated response. When granisetron was co-incubated in vitro with ZnPPIX, the ZnPPIX-mediated decrease in colon contractile response to EFS was lost. On the other hand, co-incubation of granisetron and CORM-3 (400 μmol/L) further increased the colon’s contractile response to EFS (at 5 Hz: P = 0.007; at 10 Hz: P = 0.001) and to ACh (ACh 10 μmol/L: P = 0.001; ACh 100 μmol/L: P = 0.001) elicited by CORM-3 alone. L-NNA co-administered with granisetron and CORM-3 abolished the potentiating effect of CORM-3 on granisetron on both the EFS-induced and ACh-induced contractile response.CONCLUSIONTaken together, findings from in vivo and in vitro studies suggest that the HO/CO pathway is involved in the constipating effects of granisetron.

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Section: Discussionsupporting

confidence: 62%

Carbon monoxide contributes to the constipating effects of granisetron in rat colon

Nacci¹,

Fanelli²,

Potenza³

et al. 2016

WJG

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“…Within the wall of the gut, 5-HT acts as a paracrine signaling molecule and as a neurotransmitter to initiate and modify the major regulatory functions of the gut, namely motility, secretion, and vasodilation. These conventional actions of 5-HT have been the topic of many investigations and review articles, including a recent overview in this journal 3 , and it should be noted that the roles of 5-HT in intestinal motility are still rather controversial, as debated in recent Crosstalk articles in The Journal of Physiology 4,5 . This review focuses on some of the recently discovered non-neuronal, and less conventional, roles of peripheral serotonin both within the gut wall and in other peripheral tissues.…”

mentioning

confidence: 99%

Non-conventional features of peripheral serotonin signalling — the gut and beyond

Spohn

Mawe

2017

Nat Rev Gastroenterol Hepatol

215

198

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Serotonin was first discovered in the gut, and its conventional actions as an intercellular signaling molecule in the intrinsic and extrinsic enteric reflexes are well recognized, as are a number of serotonin signaling pharmacotherapeutic targets for treatment of nausea, diarrhea, or constipation. Recent discoveries have greatly broadened our understanding of non-conventional actions of peripheral serotonin within the GI tract and in a number of other tissues. For example, it is now clear that bacteria within the lumen of the bowel influence serotonin synthesis and release by enterochromaffin cells. Also, serotonin can act both as a pro- and anti-inflammatory signaling molecule in the intestinal mucosa via activation of 5-HT7 or 5-HT4 receptors, respectively. For decades, serotonin receptors have been known to exist in a variety of tissues outside of the gut, but recent studies have provided strong evidence for physiological roles of serotonin in several important processes, including hematopoiesis, metabolic homeostasis, and bone metabolism. Furthermore, there is emerging evidence for serotonin synthesis in peripheral tissues outside of the gut. In this review, we expand the discussion beyond GI functions to highlight the roles of peripheral serotonin in colitis, hematopoiesis, energy and bone metabolism, and how serotonin is influenced by the gut microbiome.

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“…Gut‐derived serotonin (GDS) is involved in a number of endocrine roles including blood clotting, liver regeneration, bone formation (Karsenty and Gershon, ), embryo development (Cote et al, ), glucose homeostasis (Sumara et al, ) and thermogenesis (Crane et al, ; Young et al, ). GDS plays an important paracrine role in the gastrointestinal (GI) tract by activating peristaltic and secretory reflexes as well as extrinsic sensory nerves (Gershon and Tack, ; Keating and Spencer, , ; Spencer et al, , ). GDS release is elevated in inflammatory bowel disorders such as Crohn's disease (Kidd et al, ) or experimental models of colitis (Bertrand et al, ) and 5‐HT availability is a negative effector of the severity of inflammation in rodent models of IBD (Ghia et al, ; Haub et al, ).…”

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confidence: 99%

Fusion Pore Size Limits 5-HT Release From Single Enterochromaffin Cell Vesicles

et al. 2015

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Enterochromaffin cells are the major site of serotonin (5-HT) synthesis and secretion providing ∼95% of the body's total 5-HT. 5-HT can act as a neurotransmitter or hormone and has several important endocrine and paracrine roles. We have previously demonstrated that EC cells release small amounts of 5-HT per exocytosis event compared to other endocrine cells. We utilized a recently developed method to purify EC cells to demonstrate the mechanisms underlying 5-HT packaging and release. Using the fluorescent probe FFN511, we demonstrate that EC cells express VMAT and that VMAT plays a functional role in 5-HT loading into vesicles. Carbon fiber amperometry studies illustrate that the amount of 5-HT released per exocytosis event from EC cells is dependent on both VMAT and the H(+)-ATPase pump, as demonstrated with reserpine or bafilomycin, respectively. We also demonstrate that increasing the amount of 5-HT loaded into EC cell vesicles does not result in an increase in quantal release. As this indicates that fusion pore size may be a limiting factor involved, we compared pore diameter in EC and chromaffin cells by assessing the vesicle capture of different-sized fluorescent probes to measure the extent of fusion pore dilation. This identified that EC cells have a reduced fusion pore expansion that does not exceed 9 nm in diameter. These results demonstrate that the small amounts of 5-HT released per fusion event in EC cells can be explained by a smaller fusion pore that limits 5-HT release capacity from individual vesicles.

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CrossTalk opposing view: 5‐HT is not necessary for peristalsis

Cited by 49 publications

References 30 publications

Carbon monoxide contributes to the constipating effects of granisetron in rat colon

Carbon monoxide contributes to the constipating effects of granisetron in rat colon

Non-conventional features of peripheral serotonin signalling — the gut and beyond

Fusion Pore Size Limits 5-HT Release From Single Enterochromaffin Cell Vesicles

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