Differential actions of peripheral corticotropin-releasing factor (CRF), urocortin II, and urocortin III on gastric emptying and colonic transit in mice:: Role of CRF receptor subtypes 1 and 2

Peripheral CRF inhibits gastric emptying and stimulates colonic motor function in rats. We investigated the role of CRF1 and CRF2 receptors in i.p. CRF-induced alterations of gut transit in conscious mice using selective CRF1 and CRF2 ligands injected i.p. Gastric emptying 2 h after ingestion of a solid chow meal and colonic transit (time to expel a bead inserted into the distal colon) were determined simultaneously. Rat/human (r/h)CRF, which has CRF1 > CRF2 binding affinity, decreased distal colonic transit time at lower doses (6-12 mug/kg) than those inhibiting gastric emptying (20-60 mug/kg). Ovine CRF, a preferential CRF1 receptor agonist (6-60 mug/kg), reduced significantly the colonic transit time without altering gastric emptying, whereas the selective CRF2 receptor agonists mouse urocortin II (20-60 mug/kg) and urocortin III (120 mug/kg) inhibited significantly gastric emptying without modifying colonic transit. The CRF1/CRF2 receptor antagonist, astressin (30-120 mug/kg), dose dependently prevented r/hCRF (20 mug/kg)-induced inhibition of gastric emptying and reduction of colonic transit time. The selective CRF1 receptor antagonists, NBI-27914 (C18H20Cl4N4C7H8O3S) and CP-154,526 (butyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d] pyrimidin-4-yl]ethylamine) (5-30 mg/kg), dose dependently blocked r/hCRF action on the colon without influencing the gastric response, whereas the CRF2 receptor antagonist, antisauvagine-30 (30-100 mug/kg), dose dependently abolished r/hCRF-induced delayed gastric emptying and had no effect on colonic response. These data show that i.p. r/hCRF-induced opposite actions on upper and lower gut transit in conscious mice are mediated by different CRF receptor subtypes: the activation of CRF1 receptors stimulates colonic propulsive activity, whereas activation of CRF2 receptors inhibits gastric emptying.