Emerging receptor target in the pharmacotherapy of irritable bowel syndrome with constipation

Abstract

Preclinical experiments in rodent models have recently provided new information on the mechanisms underlying pain sensation in chronic visceral hypersensitivity, as well as insights into the mechanism of action of new drugs targeting abdominal pain in irritable bowel syndrome (IBS). This article describes the evidence base supporting the role of guanylate cyclase C (GC-C) activation in the modulation of gastrointestinal transit and, in particular, in visceral hypersensitivity. We propose that GC-C activation represents an important emerging target for pharmacotherapy in IBS with constipation (IBS-C), particularly given the recent regulatory approval of the GC-C agonist linaclotide as a treatment for IBS-C. More specifically, we address the following questions: “How is pain transmitted from the colon?”; “How is abdominal pain increased in IBS-C?”; “How can we reduce IBS-related abdominal pain – what drugs have been developed?”; “Does linaclotide reduce abdominal pain in animals and humans?”; and “How does linaclotide reduce abdominal pain?”

Keywords::

• abdominal pain
• constipation
• cyclic GMP
• guanylate cyclase C
• irritable bowel syndrome
• linaclotide

Financial & competing interests disclosure

LA Blackshaw has received grant/research support from AstraZeneca, Ironwood Pharmaceuticals, Inc. and Steigerwald. He has also been a speaker for Almirall. SM Brierley has received grant/research support from Ironwood Pharmaceuticals, Inc., Tioga Pharmaceuticals, Inc. and GlaxoSmithKline. He has also served as an advisory board member for Ironwood Pharmaceuticals, Inc. SM Brierley is supported by a National Health and Medical Research Council Career Development Fellowship and by National Health and Medical Research Council Australia Project Grant funding. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Medical writing assistance was provided by S Feaver of Complete Medical Communications Ltd and was funded by Almirall.