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Background & Aims: Corticotropin-releasing factor (CRF) signaling pathways play a key role in the stress response through the activation of CRF"1 and CRF"2 receptors. We investigated the CRF receptor subtypes involved in gastric postoperative ileus. Methods: Adult male mice (C57BL/6, CRF"1-deficient, and wild-type), fasted for 16-18 hours, were anesthetized for 10 minutes and had a midline celiotomy and cecal exteriorization and palpation for 30 or 60 seconds or no surgery (sham). Phenol red was given by gavage 100 minutes after anesthesia; 20 minutes later, gastric emptying and blood glucose level were measured. Results: In C57BL/6 mice, cecal palpation for 30 or 60 seconds significantly reduced gastric emptying to 30.3% +/- 1.4% and 5.8% +/- 3.4%, respectively, compared with 58.5% +/- 4.4% in sham. The CRF"1 antagonist CP-154,526 (20 mg/kg subcutaneously) completely prevented the 30-second cecal palpation-induced delayed gastric emptying (53.0% +/- 7.9% vs. 28.0% +/- 4.0% in vehicle + surgery), whereas the CRF"2 antagonist astressin"2-B injected subcutaneously had no effect. In CRF"1-deficient mice, cecal palpation for 30 seconds did not delay gastric emptying (80.3% +/- 4.5% compared with 84.7% +/- 6.3% in sham); in wild-type mice, gastric emptying was decreased to 17.8% +/- 16.1% (P < 0.05 vs. sham 72.0% +/- 12.4%). Surgery increased glucose levels by 46% compared with sham in wild-type mice, while glycemia was not altered in CRF"1-deficient mice. Basal emptying was similar in wild-type and CRF"1-deficient mice and not influenced by CRF antagonists in C57BL/6 mice. Conclusions: These data show that CRF"1 activation plays an important role in mediating the early phase of gastric ileus.