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https://hdl.handle.net/2440/82664
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Type: | Journal article |
Title: | Linaclotide inhibits colonic nociceptors and relieves abdominal pain via guanylate cyclase-c and extracellular cyclic guanosine 3′,5′-monophosphate |
Other Titles: | Linaclotide inhibits colonic nociceptors and relieves abdominal pain via guanylate cyclase-c and extracellular cyclic guanosine 3',5'-monophosphate |
Author: | Castro, J. Harrington, A. Hughes, P. Martin, C. Ge, P. Shea, C. Jin, H. Jacobson, S. Hannig, G. Mann, E. Cohen, M. MacDougall, J. Lavins, B. Kurtz, C. Silos-Santiago, I. Johnston, J. Blackshaw, L. Brierley, S. |
Citation: | Gastroenterology, 2013; 145(6):1334-1346 |
Publisher: | W B Saunders Co |
Issue Date: | 2013 |
ISSN: | 0016-5085 1528-0012 |
Statement of Responsibility: | Joel Castro, Andrea M. Harrington, Patrick A. Hughes, Christopher M. Martin, Pei Ge, Courtney M. Shea, Hong Jin, Sarah Jacobson, Gerhard Hannig, Elizabeth Mann, Mitchell B. Cohen, James E. MacDougall, Bernard J. Lavins, Caroline B. Kurtz, Inmaculada Silos-Santiago, Jeffrey M. Johnston, Mark G. Currie, L. Ashley Blackshaw, and Stuart M. Brierley |
Abstract: | <h4>Background & aims</h4>Linaclotide is a minimally absorbed agonist of guanylate cyclase-C (GUCY2C or GC-C) that reduces symptoms associated with irritable bowel syndrome with constipation (IBS-C). Little is known about the mechanism by which linaclotide reduces abdominal pain in patients with IBS-C.<h4>Methods</h4>We determined the effects of linaclotide on colonic sensory afferents in healthy mice and those with chronic visceral hypersensitivity. We assessed pain transmission by measuring activation of dorsal horn neurons in the spinal cord in response to noxious colorectal distention. Levels of Gucy2c messenger RNA were measured in tissues from mice using quantitative reverse transcription polymerase chain reaction and in situ hybridization. We used human intestinal cell lines to measure release of cyclic guanosine-3',5'-monophosphate (cGMP) by linaclotide. We performed a post-hoc analysis of data from a phase III, double-blind, parallel-group study in which 805 patients with IBS-C were randomly assigned to groups given an oral placebo or 290 μg linaclotide once daily for 26 weeks. We quantified changes in IBS-C symptoms, including abdominal pain.<h4>Results</h4>In mice, linaclotide inhibited colonic nociceptors with greater efficacy during chronic visceral hypersensitivity. Intra-colonic administration of linaclotide reduced signaling of noxious colorectal distention to the spinal cord. The colonic mucosa, but not neurons, was found to express linaclotide's target, GC-C. The downstream effector of GC-C, cGMP, was released after administration of linaclotide and also inhibited nociceptors. The effects of linaclotide were lost in Gucy2c(-/-) mice and prevented by inhibiting cGMP transporters or removing the mucosa. During 26 weeks of linaclotide administration, a significantly greater percentage of patients (70%) had at least a 30% reduction in abdominal pain compared with patients given placebo (50%).<h4>Conclusions</h4>We have identified an analgesic mechanism of linaclotide: it activates GC-C expressed on mucosal epithelial cells, resulting in the production and release of cGMP. This extracellular cGMP acts on and inhibits nociceptors, thereby reducing nociception. We also found that linaclotide reduces chronic abdominal pain in patients with IBS-C. |
Keywords: | Colon Nociceptors Cell Line Caco-2 Cells Animals Mice, Inbred C57BL Mice, Knockout Humans Mice Irritable Bowel Syndrome Disease Models, Animal Abdominal Pain Trinitrobenzenesulfonic Acid Natriuretic Peptides Guanylate Cyclase Peptides Receptors, Atrial Natriuretic Factor Receptors, Peptide Cyclic GMP Treatment Outcome Double-Blind Method Adult Aged Aged, 80 and over Middle Aged Female Male Receptors, Guanylate Cyclase-Coupled Receptors, Enterotoxin |
Rights: | © 2013 AGA Institute |
DOI: | 10.1053/j.gastro.2013.08.017 |
Grant ID: | ARC |
Published version: | https://www.clinicalkey.com.au/#!/ContentPlayerCtrl/doPlayContent/1-s2.0-S0016508513011906/ |
Appears in Collections: | Aurora harvest 4 Medicine publications |
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