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 CRF(1) and CRF(2) receptors in i.p. CRF-induced alterations of gut transit in conscious mice using selective CRF(1) and CRF(2) 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 CRF(1) > CRF(2) binding affinity, decreased distal colonic transit time at lower doses (6-12 microg/kg) than those inhibiting gastric emptying (20-60 microg/kg). Ovine CRF, a preferential CRF(1) receptor agonist (6-60 microg/kg), reduced significantly the colonic transit time without altering gastric emptying, whereas the selective CRF(2) receptor agonists mouse urocortin II (20-60 microg/kg) and urocortin III (120 microg/kg) inhibited significantly gastric emptying without modifying colonic transit. The CRF(1)/CRF(2) receptor antagonist, astressin (30-120 microg/kg), dose dependently prevented r/hCRF (20 microg/kg)-induced inhibition of gastric emptying and reduction of colonic transit time. The selective CRF(1) receptor antagonists, NBI-27914 (C(18)H(20)Cl(4)N(4)C(7)H(8)O(3)S) 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 CRF(2) receptor antagonist, antisauvagine-30 (30-100 microg/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 CRF(1) receptors stimulates colonic propulsive activity, whereas activation of CRF(2) receptors inhibits gastric emptying.