title: Activation of guanylate cyclase-C attenuates stretch responses and sensitization of mouse colorectal afferents.
abstract: Irritable bowel syndrome (IBS) is characterized by altered bowel habits, persistent pain and discomfort, and typically colorectal hypersensitivity. Linaclotide, a peripherally restricted 14 aa peptide approved for the treatment of IBS with constipation, relieves constipation and reduces IBS-associated pain in these patients presumably by activation of guanylate cyclase-C (GC-C), which stimulates production and release of cyclic guanosine monophosphate (cGMP) from intestinal epithelial cells. We investigated whether activation of GC-C by the endogenous agonist uroguanylin or the primary downstream effector of that activation, cGMP, directly modulates responses and sensitization of mechanosensitive colorectal primary afferents. The distal 2 cm of mouse colorectum with attached pelvic nerve was harvested and pinned flat mucosal side up for in vitro single-fiber recordings, and the encoding properties of mechanosensitive afferents (serosal, mucosal, muscular, and muscular-mucosal; M/M) to probing and circumferential stretch studied. Both cGMP (10-300 μM) and uroguanylin (1-1000 nM) applied directly to colorectal receptive endings significantly reduced responses of muscular and M/M afferents to stretch; serosal and mucosal afferents were not affected. Sensitized responses (i.e., increased responses to stretch) of muscular and M/M afferents were reversed by cGMP, returning responses to stretch to control. Blocking the transport of cGMP from colorectal epithelia by probenecid, a mechanism validated by studies in cultured intestinal T84 cells, abolished the inhibitory effect of uroguanylin on M/M afferents. These results suggest that GC-C agonists like linaclotide alleviate colorectal pain and hypersensitivity by dampening stretch-sensitive afferent mechanosensitivity and normalizing afferent sensitization.
authors.affiliation: Center for Pain Research, Department of Anesthesiology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA. ngb@upmc.edu
authors.forename: Bin
authors.initials: B
authors.lastname: Feng
authors.forename: Michael E
authors.initials: ME
authors.lastname: Kiyatkin
authors.forename: Jun-Ho
authors.initials: JH
authors.lastname: La
authors.forename: Pei
authors.initials: P
authors.lastname: Ge
authors.forename: Robert
authors.initials: R
authors.lastname: Solinga
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Silos-Santiago
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Gebhart
mesh_terms: D000344:Afferent Pathways / Q000201:enzymology; D000818:Animals; D045744:Cell Line, Tumor; D003106:Colon / Q000201:enzymology* / Q000294:innervation; D004789:Enzyme Activation / Q000502:physiology; D006162:Guanylate Cyclase / Q000378:metabolism*; D006801:Humans; D008297:Male; D008465:Mechanoreceptors / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D012007:Rectum / Q000201:enzymology* / Q000294:innervation
chemical_list: D006162:Guanylate Cyclase