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

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.

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.

Male mice demonstrated a significantly higher baseline I_sc than female in both WT and Crhr2^-/- genotypes. CRF and UCN1-3 (1 μM) caused greater increases in colonic I_sc (ΔI_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 ΔI_sc than CRF and stressin1. UCN2- and UCN3-evoked ΔI_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.

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.