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Linaclotide inhibits colonic nociceptors and relieves abdominal pain via guanylate cyclase-C and extracellular cyclic guanosine 3',5'-monophosphate.
Gastroenterology 2013; 145(6):1334-46.e1-11G

Abstract

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 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.

Authors+Show Affiliations

Nerve-Gut Research Laboratory, Discipline of Medicine, Faculty of Health Sciences, The University of Adelaide, Adelaide, South Australia, Australia; Department of Gastroenterology and Hepatology, Hanson Institute, Royal Adelaide Hospital, Adelaide, South Australia, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial, Phase III
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23958540

Citation

Castro, Joel, et al. "Linaclotide Inhibits Colonic Nociceptors and Relieves Abdominal Pain Via Guanylate cyclase-C and Extracellular Cyclic Guanosine 3',5'-monophosphate." Gastroenterology, vol. 145, no. 6, 2013, pp. 1334-46.e1-11.
Castro J, Harrington AM, Hughes PA, et al. Linaclotide inhibits colonic nociceptors and relieves abdominal pain via guanylate cyclase-C and extracellular cyclic guanosine 3',5'-monophosphate. Gastroenterology. 2013;145(6):1334-46.e1-11.
Castro, J., Harrington, A. M., Hughes, P. A., Martin, C. M., Ge, P., Shea, C. M., ... Brierley, S. M. (2013). Linaclotide inhibits colonic nociceptors and relieves abdominal pain via guanylate cyclase-C and extracellular cyclic guanosine 3',5'-monophosphate. Gastroenterology, 145(6), pp. 1334-46.e1-11. doi:10.1053/j.gastro.2013.08.017.
Castro J, et al. Linaclotide Inhibits Colonic Nociceptors and Relieves Abdominal Pain Via Guanylate cyclase-C and Extracellular Cyclic Guanosine 3',5'-monophosphate. Gastroenterology. 2013;145(6):1334-46.e1-11. PubMed PMID: 23958540.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Linaclotide inhibits colonic nociceptors and relieves abdominal pain via guanylate cyclase-C and extracellular cyclic guanosine 3',5'-monophosphate. AU - Castro,Joel, AU - Harrington,Andrea M, AU - Hughes,Patrick A, AU - Martin,Christopher M, AU - Ge,Pei, AU - Shea,Courtney M, AU - Jin,Hong, AU - Jacobson,Sarah, AU - Hannig,Gerhard, AU - Mann,Elizabeth, AU - Cohen,Mitchell B, AU - MacDougall,James E, AU - Lavins,Bernard J, AU - Kurtz,Caroline B, AU - Silos-Santiago,Inmaculada, AU - Johnston,Jeffrey M, AU - Currie,Mark G, AU - Blackshaw,L Ashley, AU - Brierley,Stuart M, Y1 - 2013/08/16/ PY - 2013/05/06/received PY - 2013/08/02/revised PY - 2013/08/13/accepted PY - 2013/8/21/entrez PY - 2013/8/21/pubmed PY - 2014/2/25/medline KW - Analgesia KW - CRD KW - CVH KW - DH KW - GC-C KW - IBS KW - IBS-C KW - IR KW - Signaling Transduction KW - TNBS KW - cGMP KW - chronic visceral hypersensitivity KW - colorectal distention KW - cyclic guanosine-3′,5′-monophosphate KW - dorsal horn KW - guanylate cyclase-C KW - immunoreactivity KW - irritable bowel syndrome KW - irritable bowel syndrome with constipation KW - pERK KW - phosphorylated MAP kinase ERK 1/2 KW - trinitrobenzene sulfonic acid SP - 1334-46.e1-11 JF - Gastroenterology JO - Gastroenterology VL - 145 IS - 6 N2 - 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 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. SN - 1528-0012 UR - https://www.unboundmedicine.com/medline/citation/23958540/Linaclotide_inhibits_colonic_nociceptors_and_relieves_abdominal_pain_via_guanylate_cyclase_C_and_extracellular_cyclic_guanosine_3'5'_monophosphate_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(13)01190-6 DB - PRIME DP - Unbound Medicine ER -