Effects of stress-related peptides on chloride secretion in the mouse proximal colon

Background Stress increases intestinal secretion and exacerbates symptoms of irritable bowel syndrome (IBS). Peripherally derived corticotropin-releasing factor (CRF) is known to mediate stress-induced intestinal secretion, presumably by activation of CRF1 receptors in the gut. The present study aimed to ascertain the role of CRF2 activation in intestinal secretion by three other members of CRF peptide family, urocortin (UCN) 1-3, in wild type (WT) and CRF2 knockout (Crhr2(-/-)) mice. Methods Mucosal/submucosal preparations from proximal colon of WT and Crhr2(-/-) mice of both sexes were mounted in Ussing chambers for measurement of short-circuit current (I-sc) as an indicator of ion secretion. Key Results Male mice demonstrated a significantly higher baseline I-sc than female in both WT and Crhr2(-/-) genotypes. CRF and UCN1-3 (1 mu M) caused greater increases in colonic I-sc (Delta I-sc) in male than female. Colonic I-sc response to the selective CRF1 agonist, stressin1, was similar in both sexes. In male mice, the selective CRF2 agonists (UCN2 and UCN3) caused significantly greater Delta I-sc than CRF and stressin1. UCN2- and UCN3-evoked Delta I-SC was significantly reduced in preparations pretreated with the selective CRF2 antagonist antisauvagine-30 and in Crhr2(-/-) mice. The prosecretory effects of urocortins were due to increases in Cl- secretion and involved enteric neurons and mast cells. Conclusions and Inference The findings revealed sex differences in baseline colonic secretion and responses to stress-related peptides. CRF2 receptors play a more prominent role in colonic secretion in male mice. The greater baseline secretion and responses to UCNs may contribute to the higher prevalence of diarrhea-predominant IBS in males.