Linaclotide Inhibits Colonic Nociceptors and Relieves Abdominal Pain via Guanylate Cyclase-C and Extracellular Cyclic Guanosine 3′,5′-Monophosphate

dc.contributor.authorCastro, Joel
dc.contributor.authorHarrington, Ann Chrystine
dc.contributor.authorHughes, Patrick A
dc.contributor.authorMartin, Christopher M
dc.contributor.authorGe, Pei
dc.contributor.authorShea, Courtney M
dc.contributor.authorJin, Hong
dc.contributor.authorJacobson, Sarah
dc.contributor.authorHannig, Gherhard
dc.contributor.authorMann, Elizabeth
dc.contributor.authorCohen, Mitchell B
dc.contributor.authorMacdougall, James E
dc.contributor.authorLavins, Bernard J
dc.contributor.authorKurtz, Caroline B
dc.contributor.authorSilos-Santiago, Inmaculada
dc.contributor.authorJohnson, Jeffrey M
dc.contributor.authorCurrie, Mark G
dc.contributor.authorBlackshaw, L Ashley
dc.contributor.authorBrierley, Stuart M
dc.descriptionOpen access under CC BY-NC-ND license.en
dc.description.abstractBackground & Aims 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. Methods 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. Results 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%). Conclusions 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.en
dc.identifier.citationCastro, Harrington, Hughes, Martin, Ge, Shea, . . . Brierley. (2013). Linaclotide Inhibits Colonic Nociceptors and Relieves Abdominal Pain via Guanylate Cyclase-C and Extracellular Cyclic Guanosine 3′,5′-Monophosphate. Gastroenterology, 145(6), 1334-1346.e11.en
dc.rights© 2013 by the AGA Instituteen
dc.rights.holderAGA Instituteen
dc.titleLinaclotide Inhibits Colonic Nociceptors and Relieves Abdominal Pain via Guanylate Cyclase-C and Extracellular Cyclic Guanosine 3′,5′-Monophosphateen
local.contributor.authorOrcidLookupBrierley, Stuart M:
local.contributor.authorOrcidLookupHarrington, Ann Chrystine:
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