title: 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.affiliation: Ironwood Pharmaceuticals, Inc., Cambridge, MA, USA Department of Neuro-Gastroenterology and Nutrition Toxalim, UMR 131 INRA/EI-Purpan, Toulouse, France Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Silos-Santiago
authors.forename: Gerhard
authors.initials: G
authors.lastname: Hannig
authors.forename: Helene
authors.initials: H
authors.lastname: Eutamene
authors.forename: Elena E
authors.initials: EE
authors.lastname: Ustinova
authors.forename: Sylvie G
authors.initials: SG
authors.lastname: Bernier
authors.forename: Pei
authors.initials: P
authors.lastname: Ge
authors.forename: Christopher
authors.initials: C
authors.lastname: Graul
authors.forename: Sarah
authors.initials: S
authors.lastname: Jacobson
authors.forename: Hong
authors.initials: H
authors.lastname: Jin
authors.forename: Elaine
authors.initials: E
authors.lastname: Liong
authors.forename: Marco M
authors.initials: MM
authors.lastname: Kessler
authors.forename: Tammi
authors.initials: T
authors.lastname: Reza
authors.forename: Samuel
authors.initials: S
authors.lastname: Rivers
authors.forename: Courtney
authors.initials: C
authors.lastname: Shea
authors.forename: Boris
authors.initials: B
authors.lastname: Tchernychev
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Bryant
authors.forename: Caroline B
authors.initials: CB
authors.lastname: Kurtz
authors.forename: Lionel
authors.initials: L
authors.lastname: Bueno
authors.forename: Michael A
authors.initials: MA
authors.lastname: Pezzone
authors.forename: Mark G
authors.initials: MG
authors.lastname: Currie
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000117:Acetylglucosamine / Q000031:analogs & derivatives / Q000494:pharmacology; D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D003092:Colitis / Q000139:chemically induced / Q000150:complications; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000473:pathology; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation; D005260:Female; D005767:Gastrointestinal Diseases / Q000150:complications / Q000209:etiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006162:Guanylate Cyclase / Q000378:metabolism*; D006801:Humans; D006930:Hyperalgesia / Q000503:physiopathology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism; D009020:Morphine / Q000627:therapeutic use; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D045265:Natriuretic Peptides / Q000378:metabolism* / Q000627:therapeutic use; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012149:Restraint, Physical; D015398:Signal Transduction / Q000502:physiology*; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D059265:Visceral Pain / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*
chemical_list: D000109:Acetylcholine; D000117:Acetylglucosamine; D006152:Cyclic GMP; D006162:Guanylate Cyclase; D009020:Morphine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D045265:Natriuretic Peptides; D029362:Organic Anion Transporters, Sodium-Independent; D009195:Peroxidase; D012333:RNA, Messenger; D014302:Trinitrobenzenesulfonic Acid; C073492:ABCC4 protein, human; C120809:ABCC5 protein, human; C490280:SLC22A7 protein, human; C084362:uroguanylin; C016276:8-bromocyclic GMP; C014124:4-nitrophenyl-N-acetyl-2-deoxyglucopyranoside
keywords: Cyclic guanosine monophosphate; Gastrointestinal pain; Guanylate cyclase-C; Linaclotide; Uroguanylin