Turkish Journal of Medical Sciences




Medication overuse is common among chronic migraine patients and nonsteroidal antiinflammatory drugs (NSAIDs)are the most frequently overused drugs. The pathophysiological mechanisms underlying medication overuse headache (MOH) are notcompletely understood. Intestinal hyperpermeability and leaky gut are reported in patients using NSAIDs. The aim of the study is toinvestigate the role of leaky gut and inflammation in an MOH model MOH model in male rats.Methods: The study was conducted in male Sprague Dawley rats. There were two experimental groups. The first group was the chronicNSAID group in which the rats received mefenamic acid (n = 8) for four weeks intraperitoneally (ip) and the second group was thevehicle group (n = 8) that received 5% dimethyl sulfoxide+sesame oil (ip) for 4 weeks. We assessed spontaneous pain-like behavior,periorbital mechanical withdrawal thresholds, and anxiety-like behavior using an elevated plus maze test. After behavioral testing,serum levels of occludin and lipopolysaccharide-binding protein (LBP) and brain levels of IL-17, IL-6, and high mobility group box 1protein (HMGB1) were evaluated with ELISA.Results: Serum LBP and occludin levels and brain IL-17 and HMGB1 levels were significantly elevated in the chronic NSAID groupcompared to its vehicle (p = 0.006, p = 0.016, p = 0.016 and p = 0.016 respectively) while brain IL-6 levels were comparable (p = 0.67)between the groups. The chronic NSAID group showed pain-like and anxiety-like behavior in behavioral tests. Brain IL-17 level waspositively correlated with number of head shakes (r = 0.64, p = 0.045), brain IL-6 level was negatively correlated with periorbitalmechanical withdrawal thresholds (r = –0.71, p = 0.049), and serum occludin level was positively correlated with grooming duration (r= 0.73, p = 0.032) in chronic NSAID group.Conclusion: Elevated serum occludin and LBP levels and brain IL-17 and HMGB1 levels indicate a possible role of leaky gut andinflammation in an MOH model in male rats. Additionally, a significant correlation between pain behavior and markers of inflammationand intestinal hyperpermeability, supports the role of inflammation and leaky gut in MOH pathophysiology.


Medication overuse headache, leaky gut, inflammation, occludin, lipopolysaccharide binding protein, high mobility group box protein 1

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