Repurposing Cimetidine as a Therapeutic Candidate for Irritable Bowel Syndrome in a Rat Model

Background: Visceral hypersensitivity and impaired intestinal barrier function are hallmark features of irritable bowel syndrome (IBS), linked to activation of corticotropin-releasing factor (CRF), Toll-like Receptor 4 (TLR4), and proinflammatory cytokine pathways. Cimetidine, a classical H₂ blocker, has been shown to inhibit Na⁺/H⁺ exchangers (NHEs), thereby potentially suppressing proinflammatory cytokine release.

Objectives: This study examined whether cimetidine alleviates visceral hypersensitivity and colonic hyperpermeability in rat models of IBS.

Methods: Visceral pain threshold in response to colonic balloon distention was assessed by electromyographic detection of abdominal muscle contractions during colonic balloon distention, and colonic permeability was measured using Evans blue uptake in LPS- and CRF-induced IBS models in male Sprague-Dawley rats.

Results: Intragastric cimetidine (20-100 mg/kg daily for 3 days) prevented LPS-induced visceral hypersensitivity and colonic hyperpermeability dose-dependently and also attenuated CRF-induced changes. In contrast, famotidine, another H₂ blocker, did not replicate these effects. Amiloride, an NHE inhibitor, mimicked cimetidine's effects, both of which were abolished by intracisternal SB-334867, an orexin 1 receptor antagonist. Furthermore, atropine, sulpiride, and N^G-nitro-L-arginine methyl ester, a nitric oxide (NO) synthesis inhibitor, but not scopolamine butylbromide, a peripheral muscarinic receptor antagonist, or domperidone, a peripheral dopamine D₂ receptor antagonist, blocked cimetidine's action.

Conclusion: These findings suggest that cimetidine prevents visceral hypersensitivity and colonic hyperpermeability in IBS models through mechanisms involving central orexin signaling possibly triggered by NHE inhibition, NO, and central muscarinic and dopamine D₂ receptor pathways. These findings may provide a basis for future therapeutic approaches targeting IBS.

Na+/H+ exchangers; cimetidine; gut barrier; irritable bowel syndrome; orexin; visceral pain.