PT - JOURNAL ARTICLE AU - Bin Feng AU - Michael E. Kiyatkin AU - Jun-Ho La AU - Pei Ge AU - Robert Solinga AU - Inmaculada Silos-Santiago AU - Gerald F. Gebhart TI - Activation of Guanylate Cyclase-C Attenuates Stretch Responses and Sensitization of Mouse Colorectal Afferents AID - 10.1523/JNEUROSCI.5114-12.2013 DP - 2013 Jun 05 TA - The Journal of Neuroscience PG - 9831--9839 VI - 33 IP - 23 4099 - http://www.jneurosci.org/content/33/23/9831.short 4100 - http://www.jneurosci.org/content/33/23/9831.full SO - J. Neurosci.2013 Jun 05; 33 AB - 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.