Guanylate cyclase-C agonists as peripherally acting treatments of chronic visceral pain

Stuart M. Brierley, Luke Grundy, Joel Castro, Andrea M. Harrington, Gerhard Hannig, Michael Camilleri

Research output: Contribution to journalReview articlepeer-review

Abstract

Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by abdominal pain and altered bowel habit that affects ~11% of the global population. Over the past decade, preclinical and clinical studies have revealed a variety of novel mechanisms relating to the visceral analgesic effects of guanylate cyclase-C (GC-C) agonists. Here we discuss the mechanisms by which GC-C agonists target the GC-C/cyclic guanosine-3′,5′-monophosphate (cGMP) pathway, resulting in visceral analgesia as well as clinically relevant relief of abdominal pain and other sensations in IBS patients. Due to the preponderance of evidence we focus on linaclotide, a 14-amino acid GC-C agonist with very low oral bioavailability that acts within the gut. Collectively, the weight of experimental and clinical evidence supports the concept that GC-C agonists act as peripherally acting visceral analgesics.

Original languageEnglish
Pages (from-to)110-122
Number of pages13
JournalTrends in Pharmacological Sciences
Volume43
Issue number2
DOIs
Publication statusPublished or Issued - 2 Dec 2021

Keywords

  • afferents
  • cross-organ sensitization
  • cyclic guanosine monophosphate
  • irritable bowel syndrome
  • linaclotide
  • pain

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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