A. Bharucha, D. R. Linden
Mar 1, 2010
Citations
0
Influential Citations
22
Citations
Journal
Neurogastroenterology & Motility
Abstract
Ongoing clinical trials suggest that linaclotide, a first‐in‐class, 14‐amino acid peptide guanylate cyclase‐C (GC‐C) receptor agonist and intestinal secretagogue is an effective treatment for chronic constipation. A study in this issue of the Journal suggests that linaclotide also has antihyperalgesic effects in three common rat models of inflammation‐ and stress‐induced hypersensitivity (i.e., acute trinitrobenzene sulfonic acid colitis, water avoidance stress [WAS], and restraint‐induced stress) but not in naïve animals. In mice, linaclotide at least partly reduces hyperalgesia via GC‐C receptors. Dose–effect relationships of linaclotide were complicated and non‐linear. This viewpoint discusses human clinical trials with linaclotide and the results of this study. Potential mechanisms and clinical significance of these findings are explored. Collectively, these data suggest that GC‐C receptors exert other, as yet poorly understood, effects on gastrointestinal sensitivity in conditions associated with inflammation and/or stress‐induced increased intestinal permeability. However, the data need to be confirmed in humans and in long‐term animal models. Further studies are also necessary to elucidate the mechanisms as these effects cannot be explained by linaclotide’s known effects on epithelial GC‐C receptors.