A Novel Role of Cyclic GMP in Colonic Sensory Neurotransmission in Healthy and TNBS-Treated Mice

Castro, Joel; Martin, C. L.; Hughes, Patrick A.; Silos-Santiago, Ada; Kurtz, Caroline B.; Blackshaw, L. Ashley; Brierley, Stuart M.

doi:10.1016/s0016-5085(11)62229-4

Cited by 21 publications

(17 citation statements)

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“…Furthermore, linaclotide was effective in both stress‐induced, inflammatory and chronic visceral hypersensitivity models 21,22,33 . In contrast, linaclotide had no effect on guanylate cyclase‐c knockout mice suggesting that these effects on reducing visceral hypersensitivity were mediated by the release of cyclic guanosine monophosphate (GMP) 20‐23,34 . Studies in rodent models also showed an extracellular mechanism of anti‐nociception that was linked with cGMP 20,21 .…”

Section: Discussionmentioning

confidence: 99%

Randomised clinical trial: linaclotide vs placebo—a study of bi‐directional gut and brain axis

Rao

Xiang

Yan

et al. 2020

Aliment Pharmacol Ther

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Background: Linaclotide, a guanylate cyclase C agonist relieves irritable bowel syndrome with predominant constipation (IBS-C) symptoms, but how it improves pain in humans is unknown. Aims:To investigate the effects of linaclotide and placebo on the afferent and efferent gut-brain-gut signalling in IBS-C patients, in a randomised clinical trial. Methods:Patients with IBS-C (Rome III) and rectal hypersensitivity were randomised (2:1) to receive linaclotide (290 µg) or placebo for 10 weeks and undergo bi-directional gut and brain axis assessment using anorectal electrical stimulations and transcranial/transspinal-anorectal magnetic stimulations. Rectal sensations were examined by balloon distention. Assessments included abdominal pain, bowel symptoms and quality of life (QOL) scores. Primary outcomes were latencies of recto-cortical and cortico-rectal evoked potentials.Results: Thirty-nine patients participated; 26 received linaclotide and 13 received placebo. Rectal cortical evoked potentials latencies (milliseconds) were significantly prolonged with linaclotide compared to baseline (P1:Δ 19 ± 6, P < 0.005; N1:Δ 20 ± 7, P < 0.02) but not with placebo (P1:Δ 3 ± 5; N1:Δ 4.7 ± 5,P = 0.3) or between groups.The efferent cortico-anorectal and spino-anorectal latencies were unchanged. The maximum tolerable rectal volume (cc) increased significantly with linaclotide compared to baseline (P < 0.001) and placebo (Δ 29 ± 10 vs 4 ± 20, (P < 0.03). Abdominal pain decreased (P < 0.001) with linaclotide but not between groups. Complete spontaneous bowel movement frequency increased (P < 0.001), and IBS-QOL scores improved (P = 0.01) with linaclotide compared to baseline and placebo. There was no difference in overall responders between linaclotide and placebo (54% vs 23%, P = 0.13). Conclusions:Linaclotide prolongs afferent gut-brain signalling from baseline but both afferent and efferent signalling were unaffected compared to placebo. Linaclotide significantly improves rectal hypersensitivity, IBS-C symptoms and QOL compared to placebo.These mechanisms may explain the effects of linaclotide on pain relief in IBS-C patients. ClinicalTrials.Gov: Registered at Clinical trials.gov no NCT02078323.This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations.

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Section: Discussionmentioning

confidence: 99%

Randomised clinical trial: linaclotide vs placebo—a study of bi‐directional gut and brain axis

Rao

Xiang

Yan

et al. 2020

Aliment Pharmacol Ther

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“…The exact molecular mechanism of this anti-nociceptive effect of linaclotide has yet to be elucidated. Initial in vitro studies suggest it is an effect of extracellular cGMP on nociceptors found on colonic afferent pain fibers 10,14,15…”

Section: Figurementioning

confidence: 99%

Linaclotide: A New Option for the Treatment of Irritable Bowel syndrome with Constipation and Chronic Idiopathic Constipation in Adults

Parker

Yuan

Liu

2013

Clin Med Insights Gastroenterol

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Chronic idiopathic constipation (CC) and irritable bowel syndrome with predominant constipation (IBS-C) are the 2 most common conditions among functional gastrointestinal disorders. Despite current multiple therapeutic options, treatment remains challenging and dissatisfactory to many patients. Linaclotide is a novel therapeutic agent, which is a guanylate cyclase receptor agonist that stimulates water secretion from the intestinal epithelium by promoting chloride and bicarbonate efflux into the lumen through activation of the cystic fibrosis transmembrane conductance regulator. Clinical trials have demonstrated that linaclotide is effective, safe and well tolerated in patients with CC and IBS-C. This review article highlights the mechanism of action of linaclotide, reviews published literature based on a search of databases, including MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL), up to February 2013, and compares its utility with other currently available agents.

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“…Furthermore, an accompanying increase in the luminal and submucosal concentration of cGMP is observed as intracellular cGMP is transported out of epithelial cells. In animal models, decreased activity of pain-sensing afferent fibers is likely mediated by increased extracellular cGMP in the submucosa [1]. Compared to the pharmacological effects elicited by the increase in cGMP, less is known about the distribution and metabolic fate of this second messenger that is transported out into the luminal space.…”

Section: Introductionmentioning

confidence: 99%

Metabolic fate of orally administered cGMP in rats

Liong

Graul

Rivers

et al. 2013

BMC Pharmacol Toxicol

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A Novel Role of Cyclic GMP in Colonic Sensory Neurotransmission in Healthy and TNBS-Treated Mice

Cited by 21 publications

References 0 publications

Randomised clinical trial: linaclotide vs placebo—a study of bi‐directional gut and brain axis

Randomised clinical trial: linaclotide vs placebo—a study of bi‐directional gut and brain axis

Linaclotide: A New Option for the Treatment of Irritable Bowel syndrome with Constipation and Chronic Idiopathic Constipation in Adults

Metabolic fate of orally administered cGMP in rats

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