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Linaclotide - a secretagogue and antihyperalgesic agent - what next?Bharucha AE; Linden DRNeurogastroenterol Motil 2010[Mar]; 22 (3): 227-31Ongoing 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 naive 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.|Animals[MESH]|Clinical Trials as Topic[MESH]|Colon/*drug effects[MESH]|Constipation/complications/*drug therapy[MESH]|Humans[MESH]|Irritable Bowel Syndrome/complications/*drug therapy[MESH]|Peptides/*therapeutic use[MESH]|Rats[MESH] |
