Postoperative prophylactic corticotropin-releasing hormone receptor 1 (CRHR1) antagonism attenuates post-surgical peritoneal adhesion formation in a rat cecal abrasion model

Post-operative peritoneal adhesions affect up to 95% of abdominal surgery patients, driving significant morbidity, repeat interventions, and healthcare costs. No FDA-approved oral agent currently exists for their prevention. Building on our findings implicating corticotropin-releasing hormone receptor 1 (CRHR1) in adhesion formation, this study evaluated whether oral CRHR1 blockade with pexacerfont could prevent post-surgical peritoneal adhesions in a rat cecal abrasion model. Male and female Sprague-Dawley rats were randomly assigned to four groups: naïve, abrasion/kaolin-vehicle, or abrasion/kaolin-pexacerfont at 3 or 10 mg/kg (n = 15–16/group). Oral treatment began 24 hours post-surgery and continued for seven days. On postoperative day 14, animals were assessed for macroscopic and histological adhesion scores, colonic damage, fibrosis grading, mast cell counts, and nociception. Pexacerfont at 10 mg/kg significantly reduced colonic adhesion scores versus vehicle controls (p = 0.0155), restoring them to naïve levels. Macroscopic colonic damage was similarly reduced (p = 0.0097 vs. vehicle). The 3 mg/kg dose did not reach significance. Abrasion-vehicle animals showed significantly elevated cecal mast cell counts compared with naïve controls (p = 0.0113), with pexacerfont 10 mg/kg producing a 31% reduction. No sex differences in drug response were observed, and nociceptive thresholds did not differ across groups. This is the first demonstration that a selective CRHR1 antagonist can serve as an oral postoperative prophylactic against surgical adhesions. Pexacerfont's dose-dependent efficacy in both sexes, likely mediated through mast cell suppression and attenuation of pro-angiogenic signaling, positions it as a first-in-class therapeutic candidate warranting translational investigation.