Gastrointestinal pain: unraveling a novel endogenous pathway through uroguanylin/guanylate cyclase-C/cGMP activation.

Abstract

The natural hormone uroguanylin regulates intestinal fluid homeostasis and bowel function through activation of guanylate cyclase-C (GC-C), resulting in increased intracellular cyclic guanosine-3',5'-monophosphate (cGMP). We report the effects of uroguanylin-mediated activation of the GC-C/cGMP pathway in vitro on extracellular cGMP transport and in vivo in rat models of inflammation- and stress-induced visceral hypersensitivity. In vitro exposure of intestinal Caco-2 cells to uroguanylin stimulated bidirectional, active extracellular transport of cGMP into luminal and basolateral spaces. cGMP transport was significantly and concentration dependently decreased by probenecid, an inhibitor of cGMP efflux pumps. In ex vivo Ussing chamber assays, uroguanylin stimulated cGMP secretion from the basolateral side of rat colonic epithelium into the submucosal space. In a rat model of trinitrobenzene sulfonic acid (TNBS)-induced visceral hypersensitivity, orally administered uroguanylin increased colonic thresholds required to elicit abdominal contractions in response to colorectal distension (CRD). Oral administration of cGMP mimicked the antihyperalgesic effects of uroguanylin, significantly decreasing TNBS- and restraint stress-induced visceromotor response to graded CRD in rats. The antihyperalgesic effects of cGMP were not associated with increased colonic spasmolytic activity, but were linked to significantly decreased firing rates of TNBS-sensitized colonic afferents in rats in response to mechanical stimuli. In conclusion, these data suggest that the continuous activation of the GC-C/cGMP pathway along the intestinal tract by the endogenous hormones guanylin and uroguanylin results in significant reduction of gastrointestinal pain. Extracellular cGMP produced on activation of GC-C is the primary mediator in this process via modulation of sensory afferent activity.

• Authors: Inmaculada Silos-Santiago, Gerhard Hannig, Helene Eutamene, Elena E Ustinova, Sylvie G Bernier, Pei Ge, Christopher Graul, Sarah Jacobson, Hong Jin, Elaine Liong, Marco M Kessler, Tammi Reza, Samuel Rivers, Courtney Shea, Boris Tchernychev, Alexander P Bryant, Caroline B Kurtz, Lionel Bueno, Michael A Pezzone, Mark G Currie
• Journal: Pain (Pain) Vol. 154 Issue 9 Pg. 1820-1830 (Sep 2013) ISSN: 1872-6623 [Electronic] United States
• PMID: 23748116 (Publication Type: Journal Article)
• Copyright: Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Chemical References

• ABCC4 protein, human
• ABCC5 protein, human
• Multidrug Resistance-Associated Proteins
• Natriuretic Peptides
• Organic Anion Transporters, Sodium-Independent
• RNA, Messenger
• SLC22A7 protein, human
• uroguanylin
• 8-bromocyclic GMP
• 4-nitrophenyl-N-acetyl-2-deoxyglucopyranoside
• Morphine
• Trinitrobenzenesulfonic Acid
• Peroxidase
• Guanylate Cyclase
• Cyclic GMP
• Acetylcholine
• Acetylglucosamine

Topics

• Acetylcholine (pharmacology)
• Acetylglucosamine (analogs & derivatives, pharmacology)
• Adenocarcinoma (pathology)
• Animals
• Cell Differentiation (drug effects)
• Cell Line, Tumor
• Colitis (chemically induced, complications)
• Colon (drug effects, metabolism)
• Colorectal Neoplasms (pathology)
• Cyclic GMP (analogs & derivatives, metabolism, pharmacology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Interactions
• Electric Stimulation
• Female
• Gastrointestinal Diseases (complications, etiology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Guanylate Cyclase (metabolism)
• Humans
• Hyperalgesia (physiopathology)
• Intestinal Mucosa (drug effects, metabolism, physiology)
• Male
• Mast Cells (drug effects, metabolism)
• Morphine (therapeutic use)
• Multidrug Resistance-Associated Proteins (genetics, metabolism)
• Natriuretic Peptides (metabolism, therapeutic use)
• Organic Anion Transporters, Sodium-Independent (genetics, metabolism)
• Peroxidase (metabolism)
• RNA, Messenger
• Rats
• Rats, Sprague-Dawley
• Rats, Wistar
• Restraint, Physical
• Signal Transduction (physiology)
• Trinitrobenzenesulfonic Acid (toxicity)
• Visceral Pain (drug therapy, etiology, metabolism)