Gastroparesis Worsens Indomethacin-Induced Gastric Antral Ulcers by Bile Reflux via Activation of 5-HT3 and Dopamine D2 Receptors in Mice

Dig Dis Sci. 2023 Oct;68(10):3886-3901. doi: 10.1007/s10620-023-08086-x. Epub 2023 Aug 26.


Background/aims: We examined the contributions of gastric emptying and duodenogastric bile reflux in the formation of gastric antral ulcers induced by NSAIDs in mice.

Methods: We used the murine re-fed indomethacin (IND) experimental ulcer model. Outcome measures included the appearance of gastric lesions 24 h after IND treatment and the assessment of gastric contents and the concentration of bile acids 1.5 h after re-feeding. The effects of atropine, dopamine, SR57227 (5-HT3 receptor agonist), apomorphine, ondansetron, haloperidol, and dietary taurocholate and cholestyramine were also examined.

Results: IND (10 mg/kg, s.c.) induced severe lesions only in the gastric antrum in the re-fed model. The antral lesion index and the amount of food intake during the 2-h refeeding period were positively correlated. Atropine and dopamine delayed gastric emptying, increased bile reflux, and worsened IND-induced antral lesions. SR57227 and apomorphine worsened antral lesions with increased bile reflux. These effects were prevented by the anti-emetic drugs ondansetron and haloperidol, respectively. The anti-emetic drugs markedly decreased the severity of antral lesions and the increase of bile reflux induced by atropine or dopamine without affecting delayed gastric emptying. Antral lesions induced by IND were increased by dietary taurocholate but decreased by the addition of the bile acid sequestrant cholestyramine.

Conclusions: These results suggest that gastroparesis induced by atropine or dopamine worsens NSAID-induced gastric antral ulcers by increasing duodenogastric bile reflux via activation of 5-HT3 and dopamine D2 receptors.

Keywords: Atropine; Bile reflux; Gastric antral ulcer; Gastroparesis; NSAIDs.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects
  • Antiemetics* / adverse effects
  • Apomorphine / adverse effects
  • Atropine / adverse effects
  • Bile Reflux*
  • Cholestyramine Resin / adverse effects
  • Dopamine
  • Duodenogastric Reflux*
  • Gastroparesis* / chemically induced
  • Haloperidol / adverse effects
  • Indomethacin
  • Mice
  • Ondansetron / pharmacology
  • Serotonin
  • Stomach Ulcer* / chemically induced
  • Ulcer


  • Indomethacin
  • Dopamine
  • Serotonin
  • Apomorphine
  • Antiemetics
  • Ondansetron
  • Cholestyramine Resin
  • Haloperidol
  • Anti-Inflammatory Agents, Non-Steroidal
  • Atropine