VIP is involved in peripheral CRF-induced stimulation of propulsive colonic motor function and diarrhea in male rats

We investigated whether vasoactive intestinal peptide (VIP) and/or prostaglandins contribute to peripheral corticotropin-releasing factor (CRF)-induced CRF1 receptor-mediated stimulation of colonic motor function and diarrhea in rats. The VIP antagonist, [4Cl-D-Phe6, Leu17]VIP injected intraperitoneally completely prevented CRF (10 µg/kg ip)-induced fecal output and diarrhea occurring within the first hour after injection, whereas pretreatment with the prostaglandins synthesis inhibitor, indomethacin, had no effect. In submucosal plexus neurons, CRF induced significant c-Fos expression most prominently in the terminal ileum compared with duodenum and jejunum, whereas no c-Fos was observed in the proximal colon. c-Fos expression in ileal submucosa was colocalized in 93.4% of VIP-positive neurons and 31.1% of non-VIP-labeled neurons. CRF1 receptor immunoreactivity was found on the VIP neurons. In myenteric neurons, CRF induced only a few c-Fos-positive neurons in the ileum and a robust expression in the proximal colon (17.5 ± 2.4 vs. 0.4 ± 0.3 cells/ganglion in vehicle). The VIP antagonist prevented intraperitoneal CRF-induced c-Fos induction in the ileal submucosal plexus and proximal colon myenteric plexus. At 60 min after injection, CRF decreased VIP levels in the terminal ileum compared with saline (0.8 ± 0.3 vs. 2.5 ± 0.7 ng/g), whereas VIP mRNA level detected by qPCR was not changed. These data indicate that intraperitoneal CRF activates intestinal submucosal VIP neurons most prominently in the ileum and myenteric neurons in the colon. It also implicates VIP signaling as part of underlying mechanisms driving the acute colonic secretomotor response to a peripheral injection of CRF, whereas prostaglandins do not play a role. NEW & NOTEWORTHY Corticotropin-releasing factor (CRF) in the gut plays a physiological role in the stimulation of lower gut secretomotor function induced by stress. We showed that vasoactive intestinal peptide (VIP)-immunoreactive neurons in the ileal submucosal plexus expressed CRF1 receptor and were prominently activated by CRF, unlike colonic submucosal neurons. VIP antagonist abrogated CRF-induced ileal submucosal and colonic myenteric activation along with functional responses (defecation and diarrhea). These data point to VIP signaling in ileum and colon as downstream effectors of CRF.

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5-Hydroxytryptophan activates colonic myenteric neurons and propulsive motor function through 5-HT4 receptors in conscious mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00289.2006 ◽

2007 ◽

Vol 292 (1) ◽

pp. G419-G428 ◽

Cited By ~ 23

Author(s):

L. Wang ◽

V. Martínez ◽

H. Kimura ◽

Y. Taché

Keyword(s):

Motor Function ◽

Colonic Motility ◽

Distal Colon ◽

Nadph Diaphorase ◽

Maximal Response ◽

Myenteric Neurons ◽

Diaphorase Activity ◽

Colonic Motor ◽

Different Populations ◽

Fos Expression

Serotonin [5-hydroxytryptamine (5-HT)] acts as a modulator of colonic motility and secretion. We characterized the action of the 5-HT precursor 5-hydroxytryptophan (5-HTP) on colonic myenteric neurons and propulsive motor activity in conscious mice. Fos immunoreactivity (IR), used as a marker of neuronal activation, was monitored in longitudinal muscle/myenteric plexus whole mount preparations of the distal colon 90 min after an intraperitoneal injection of 5-HTP. Double staining of Fos IR with peripheral choline acetyltransferase (pChAT) IR or NADPH-diaphorase activity was performed. The injection of 5-HTP (0.5, 1, 5, or 10 mg/kg ip) increased fecal pellet output and fluid content in a dose-related manner, with a peak response observed within the first 15 min postinjection. 5-HTP (0.5–10 mg/kg) dose dependently increased Fos expression in myenteric neurons, with a maximal response of 9.9 ± 1.0 cells/ganglion [ P < 0.05 vs. vehicle-treated mice (2.3 ± 0.6 cells/ganglion)]. There was a positive correlation between Fos expression and fecal output. Of Fos-positive ganglionic cells, 40 ± 4% were also pChAT positive and 21 ± 5% were NADPH-diaphorase positive in response to 5-HTP, respectively. 5-HTP-induced defecation and Fos expression were completely prevented by pretreatment with the selective 5-HT4 antagonist RS-39604. These results show that 5-HTP injected peripherally increases Fos expression in different populations of cholinergic and nitrergic myenteric neurons in the distal colon and stimulates propulsive colonic motor function through 5-HT4 receptors in conscious mice. These findings suggest an important role of activation of colonic myenteric neurons in the 5-HT4 receptor-mediated colonic propulsive motor response.

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III. Stress-related alterations of gut motor function: role of brain corticotropin-releasing factor receptors

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.2001.280.2.g173 ◽

2001 ◽

Vol 280 (2) ◽

pp. G173-G177 ◽

Cited By ~ 191

Author(s):

Yvette Taché ◽

Vicente Martinez ◽

Mulugeta Million ◽

Lixin Wang

Keyword(s):

Irritable Bowel Syndrome ◽

Motor Function ◽

Corticotropin Releasing Factor ◽

Receptor Subtypes ◽

Upper Gi ◽

Colonic Motor ◽

Irritable Bowel ◽

Anxiety Depression ◽

Stimulation Of

Alterations of gastrointestinal (GI) motor function are part of the visceral responses to stress. Inhibition of gastric emptying and stimulation of colonic motor function are the commonly encountered patterns induced by various stressors. Activation of brain corticotropin-releasing factor (CRF) receptors mediates stress-related inhibition of upper GI and stimulation of lower GI motor function through interaction with different CRF receptor subtypes. CRF subtype 1 receptors are involved in the colonic and anxiogenic responses to stress and may have clinical relevance in the comorbidity of anxiety/depression and irritable bowel syndrome.

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Water-avoidance stress-inducedc-fos expression in the rat brain and stimulation of fecal output: role of corticotropin-releasing factor

Brain Research ◽

10.1016/0006-8993(94)91810-4 ◽

1994 ◽

Vol 641 (1) ◽

pp. 21-28 ◽

Cited By ~ 106

Author(s):

B. Bonaz ◽

Y. Taché

Keyword(s):

Rat Brain ◽

Corticotropin Releasing Factor ◽

Fecal Output ◽

Fos Expression ◽

Stimulation Of

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Peripheral corticotropin-releasing factor (CRF) stimulates fos expression in the rat colonic myenteric neurons andfecal pellet output through CRF receptor subtype 1

Gastroenterology ◽

10.1016/s0016-5085(00)84692-2 ◽

2000 ◽

Vol 118 (4) ◽

pp. A638 ◽

Cited By ~ 1

Author(s):

Marcel Miampamba ◽

Celine Maillot ◽

Mulugeta Million ◽

Yvette Tache

Keyword(s):

Corticotropin Releasing Factor ◽

Receptor Subtype ◽

Myenteric Neurons ◽

Fos Expression

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The Newly Developed CRF1-Receptor Antagonists, NGD 98-2 and NGD 9002, Suppress Acute Stress-Induced Stimulation of Colonic Motor Function and Visceral Hypersensitivity in Rats

PLoS ONE ◽

10.1371/journal.pone.0073749 ◽

2013 ◽

Vol 8 (9) ◽

pp. e73749 ◽

Cited By ~ 21

Author(s):

Mulugeta Million ◽

Jing-Fang Zhao ◽

Andrew Luckey ◽

József Czimmer ◽

George D. Maynard ◽

...

Keyword(s):

Motor Function ◽

Acute Stress ◽

Visceral Hypersensitivity ◽

Receptor Antagonists ◽

Crf1 Receptor ◽

Colonic Motor ◽

Stimulation Of

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Corticotropin-Releasing Factor and the Brain-Gut Motor Response to Stress

Canadian Journal of Gastroenterology ◽

10.1155/1999/375916 ◽

1999 ◽

Vol 13 (suppl a) ◽

pp. 18A-25A ◽

Cited By ~ 110

Author(s):

Yvette Taché ◽

Vicente Martinez ◽

Mulugeta Million ◽

Jean Rivier

Keyword(s):

Gastric Emptying ◽

Motor Function ◽

Paraventricular Nucleus ◽

Corticotropin Releasing Factor ◽

Fecal Excretion ◽

Central Administration ◽

Gastric Stasis ◽

Colonic Motor ◽

Sites Of Action ◽

The Brain

The characterization of corticotropin-releasing factor (CRF) and CRF receptors, and the development of specific CRF receptor antagonists selective for the receptor subtypes have paved the way to the understanding of the biochemical coding of stress-related alterations of gut motor function. Reports have consistently established that central administration of CRF acts in the brain to inhibit gastric emptying while stimulating colonic motor function through modulation of the vagal and sacral parasympathetic outflow in rodents. Endogenous CRF in the brain plays a role in mediating various forms of stressor-induced gastric stasis, including postoperative gastric ileus, and activates colonic transit and fecal excretion elicited by psychologically aversive or fearful stimuli. It is known that brain CRF is involved in the cross-talk between the immune and gastrointestinal systems because systemic or central administration of interleukin-1-beta delays gastric emptying while stimulating colonic motor activity through activation of CRF release in the brain. The paraventricular nucleus of the hypothalamus and the dorsal vagal complex are important sites of action for CRF to inhibit gastric motor function, while the paraventricular nucleus of the hypothalamus and the locus coeruleus complex are sites of action for CRF to stimulate colonic motor function. The inhibition of gastric emptying by CRF may be mediated by the interaction with the CRF2receptors, while the anxiogenic and colonic motor responses may involve CRF1receptors. Hypersecretion of CRF in the brain may contribute to the pathophysiology of stress-related exacerbation of irritable bowel syndrome.

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