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Activation of Guanylate Cyclase-C Attenuates Stretch Responses and Sensitization of Mouse Colorectal Afferents.
- Source :
-
Journal of Neuroscience . 6/5/2013, Vol. 33 Issue 23, p9831-9839. 9p. - Publication Year :
- 2013
-
Abstract
- Irritable bowel syndrome (IBS) is characterized by altered bowel habits, persistent pain and discomfort, and typically colorectal hyper-sensitivity. Linadotide, 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 sensi-tization 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 /AM) and urogua-nylin (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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 02706474
- Volume :
- 33
- Issue :
- 23
- Database :
- Academic Search Index
- Journal :
- Journal of Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 88094123
- Full Text :
- https://doi.org/10.1523/JNEUROSCI.5114-12.2013