Abstract
Peripheral CRF inhibits gastric emptying and stimulates colonic motor function in rats. We investigated the role of CRF1and 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 > CRF2binding affinity, decreased distal colonic transit time at lower doses (6–12 μg/kg) than those inhibiting gastric emptying (20–60 μg/kg). Ovine CRF, a preferential CRF1 receptor agonist (6–60 μg/kg), reduced significantly the colonic transit time without altering gastric emptying, whereas the selective CRF2receptor agonists mouse urocortin II (20–60 μg/kg) and urocortin III (120 μg/kg) inhibited significantly gastric emptying without modifying colonic transit. The CRF1/CRF2receptor antagonist, astressin (30–120 μg/kg), dose dependently prevented r/hCRF (20 μg/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 CRF2receptor antagonist, antisauvagine-30 (30–100 μg/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.
Footnotes
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This work was supported by the Department of Veterans Affairs Merit Review (Y.T.) and National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-57238 (Y.T.) and DK-41301 (Animal Core, Y.T.), and DK-26741 (J.R.). V. Martı́nez was partially supported by the Conselleria de Cultura Educació i Ciència de la Generalitat Valenciana (Spain).
- Abbreviations:
- CRF
- corticotropin-releasing factor
- DMSO
- dimethyl sulfoxide
- oCRF
- ovine CRF
- r/hCRF
- rat/human CRF
- Ucn
- urocortin
- mUcn II
- mouse urocortin II
- mUcn III
- mouse urocortin III
- rUcn
- rat urocortin
- Received November 9, 2001.
- Accepted January 22, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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