Medication Overuse Headache is Associated with Elevated Lipopolysaccharide Binding Protein and Pro-inflammatory Molecules in the Bloodstream

Abstract

Abstract Objective: Medication overuse headache (MOH) is secondary headache that accompanies chronic migraine and NSAIDs are the most frequently use analgesics in the word. NSAIDs are known to induce leaky gut and we aimed to investigate whether NSAID induced MOH is associated with altered circulating LBP levels and inflammatory molecules. Materials and Methods: Piroxicam (10 mg /kg, po) for 5 weeks was used to induce MOH in female Sprague Dawley rats. Pain was tested by evaluating periorbital von Frey thresholds, grooming, freezing and headshake behavior. Serum samples and brain tissues were collected to measure circulating LPS binding protein (LBP), tight junction protein occludin, adherence junction protein vascular endothelial (VE)-cadherin, CGRP, IL-6, levels. HMGB1 and IL-17 were determined in brain tissues. Results: Chronic piroxicam exposure resulted in decreased periorbital mechanical thresholds, increased grooming, freezing and headshake behavior compared to vehicle administration. Serum LBP, CGRP, IL-6, IL-17, occludin, VE-cadherin levels and brain IL-17 and HMGB1 levels were significantly higher in piroxicam group compared to controls. Serum LBP was correlated positively with occludin (r = 0.611), VE-cadherin (r = 0.588), CGRP (r = 0.706), HMGB1 (r = 0.618), headshakes (r = 0.921), and negatively with von Frey thresholds (r=-0.740). Conclusion: Chronic piroxicam induced MOH is associated with elevated serum LPS, VE- cadherin and occludin levels indicating disrupted intestinal barrier function and leakage of LPS into the systemic circulation. LPS induced low-grade inflammation and elevated nociceptive and/or pro-inflammatory molecules of HMGB1, IL-6, IL-17, CGRP and may play a role in development and maintaining of MOH. Interference with leaky gut and pro- inflammatory nociceptive molecules could also be a target for sustained management of MOH.