Restraint stress exacerbates indomethacin-induced gastric antral ulcers by gastroparesis via activation of corticotropin-releasing factor 2 receptors in refed mice.

Abstract

We examined the effects of stress on the indomethacin (IND)-induced gastric antral ulcer formation in refed mice. Male mice underwent refeeding of diet for 2 hours after a fast for 22 hours, followed by IND injection; the lesion index was measured 24 hours later. Mice also underwent a defined diet for 2 hours following a fast for 22 hours, and the stomachs were collected 1.5 hours later. We then measured the volume and the bile acid concentrations of the gastric contents. Mice underwent restraint stress (RS) in a cylindrical plastic tube for 60 minutes, or treatment with corticotropin-releasing factor (CRF), following refeeding of diet for 2 hours. We then examined the effects of RS and CRF on the lesion index, gastric emptying, and duodenogastric bile reflux. The effects of receptor antagonists for CRF₂ (astressin-2B), CRF₁, 5-hydroxytriptamine 3 (ondansetron), dopamine 2 (haloperidol), and cholecystokinin 1 (lorglumide) on the effects of RS or CRF were examined. IND (10 mg/kg, s.c.) induced pronounced lesions in the antrum. RS and CRF (30 μg/kg, i.p.) increased the severity of the antral lesions accompanied by an increase in gastric volume and concentration of bile acids. These effects of RS and peripheral CRF were significantly inhibited by pretreatment with astressin-2B, ondansetron, haloperidol, and lorglumide, but not by the CRF₁ receptor antagonist. This study suggests that RS increases the severity of IND-induced gastric antral ulcers associated with gastroparesis and enhanced bile reflux via activation of peripheral CRF₂, 5-hydroxytriptamine 3, and cholecystokinin 1 receptors with central dopamine 2 receptor, but not by CRF₁ receptor. SIGNIFICANCE STATEMENT: Restraint stress worsens nonsteroidal anti-inflammatory drugs-induced antral ulcers due to inhibition of gastric motility and increase in bile reflux via activation of peripheral corticotropin-releasing factor 2, 5-hydroxytriptamine 3, and cholecystokinin 1 receptors with central dopamine 2 receptor. Our study predicts that gastroparesis induced by antimotility drugs, stress, functional dyspepsia, Parkinson disease, diabetes mellitus, and other conditions worsens, and gastroprokinetic agents prevent the severity of nonsteroidal anti-inflammatory drugs-induced gastric antral ulcers.