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

被引：211

作者：

Castro, Joel ^{[1
,2
]}

Harrington, Andrea M. ^{[1
,2
]}

Hughes, Patrick A. ^{[1
,2
]}

Martin, Christopher M. ^{[1
]}

Ge, Pei ^{[3
]}

Shea, Courtney M. ^{[3
]}

Jin, Hong ^{[3
]}

Jacobson, Sarah ^{[3
]}

Hannig, Gerhard ^{[3
]}

Mann, Elizabeth ^{[4
]}

Cohen, Mitchell B. ^{[4
]}

MacDougall, James E. ^{[3
]}

Lavins, Bernard J. ^{[3
]}

Kurtz, Caroline B. ^{[3
]}

Silos-Santiago, Inmaculada ^{[3
]}

Johnston, Jeffrey M. ^{[3
]}

Currie, Mark G. ^{[3
]}

Blackshaw, L. Ashley ^{[1
,2
,5
]}

Brierley, Stuart M. ^{[1
,2
,5
]}

机构：

[1] Univ Adelaide, Fac Hlth Sci, Discipline Med, Nerve Gut Res Lab, Adelaide, SA, Australia

[2] Royal Adelaide Hosp, Hanson Inst, Dept Gastroenterol & Hepatol, Adelaide, SA 5000, Australia

[3] Ironwood Pharmaceut, Cambridge, MA USA

[4] Cincinnati Childrens Hosp Med Ctr, Div Gastroenterol Hepatol & Nutr, Cincinnati, OH 45229 USA

[5] Univ Adelaide, Fac Hlth Sci, Discipline Physiol, Adelaide, SA, Australia

来源：

GASTROENTEROLOGY | 2013年 / 145卷 / 06期

基金：

澳大利亚研究理事会; 英国医学研究理事会; 澳大利亚国家健康与医学研究理事会;

关键词：

CVH; CRD; Signaling Transduction; Analgesia; IRRITABLE-BOWEL-SYNDROME; GASTROINTESTINAL-TRACT; INTESTINAL SECRETION; CHRONIC CONSTIPATION; CONTROLLED-TRIAL; MICE LACKING; RECEPTOR; HYPERSENSITIVITY; AFFERENTS; ACTIVATION;

D O I：

10.1053/j.gastro.2013.08.017

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

BACKGROUND & 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 mu g 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.

引用

页码：1334 / +

页数：24