L‐Carnitine Improves Visceral Hypersensitivity and Colonic Hyperpermeability in a Rat Model of Irritable Bowel Syndrome

ABSTRACT Background Visceral hypersensitivity and impaired intestinal barrier function are key features in the pathophysiology of irritable bowel syndrome (IBS). Activation of central orexin signaling has been shown to ameliorate these gastrointestinal disturbances via vagal pathways mediated by brain orexin and central muscarinic receptors. Given that several studies suggest that L‐carnitine, a naturally occurring amino acid, can activate orexin signaling, we hypothesized that L‐carnitine attenuates these gastrointestinal abnormalities in a rat model of IBS. Methods Visceral pain thresholds to colonic balloon distension were evaluated by electromyographic recordings of abdominal muscle contractions. Colonic permeability was assessed by measuring Evans blue uptake in lipopolysaccharide (LPS) and corticotropin‐releasing factor (CRF) ‐induced IBS models in male Sprague–Dawley rats. Key Results Intragastric administration of L‐carnitine (3–200 mg kg −1 day −1 for 3 days) dose‐dependently prevented LPS‐induced visceral hypersensitivity and colonic hyperpermeability, and attenuated these changes induced by CRF. Intracisternal administration of SB‐334867, an orexin 1 receptor antagonist, abolished the effects of L‐carnitine in the LPS model. Moreover, atropine, sulpiride, a dopamine D 2 receptor antagonist, and N G ‐nitro‐L‐arginine methyl ester, a nitric oxide synthesis inhibitor, but not scopolamine butylbromide, a peripheral muscarinic receptor antagonist, blocked the effects of L‐carnitine. Additionally, compound C, an AMPK inhibitor, and GW9662, a PPAR‐γ antagonist, also abolished L‐carnitine's effects. Conclusions and Inferences L‐Carnitine prevents visceral hypersensitivity and colonic hyperpermeability in IBS models via mechanisms involving brain orexin, as well as central muscarinic, dopamine D 2 , nitric oxide, AMPK, and PPAR‐γ signaling. These findings suggest that L‐carnitine may represent a promising therapeutic option for IBS.