Akademik Veri Yönetim Sistemi
JOURNAL OF HEADACHE AND PAIN, cilt.26, sa.1, 2025 (SCI-Expanded, Scopus)
Background/AimMedication-overuse headache (MOH) is a female-predominant secondary headache generally associated with nonsteroidal anti-inflammatory drug overuse and chronification of migraine. MOH is associated with elevated serum levels of inflammatory and nociceptive molecules and intestinal leak in migraine patients. We aimed to characterize the changes in expression patterns of high mobility group box 1 (HMGB1) and hypoxia-inducible factor 1 alpha (HIF-1 alpha) in the trigeminal ganglion cells, thereby offering new insights into the molecular mechanisms contributing to MOH.MethodsMOH was induced by oral piroxicam in female Sprague Dawley rats, and pain-related behaviors were assessed via periorbital mechanical withdrawal thresholds, head-face grooming, freezing, and head shaking during the metestrus and diestrus phases. The levels, and the cell type preference and nuclear or cytoplasmic localization for the expression of HMGB1, HIF-1 alpha, calcitonin gene-related peptide (CGRP), and SULT1A1 in the trigeminal ganglia were examined using immunohistochemistry and Western blot analyses.ResultsChronic piroxicam administration decreased periorbital withdrawal thresholds and increased nociceptive behaviors. CGRP-positive neuron number and CGRP levels are increased in the TG of the MOH group. HMGB1 immunoreactivity was observed in both neurons and satellite glial cells (SGCs), with enhanced cytoplasmic translocation and elevated total protein levels in the MOH group. HIF-1 alpha was present in neurons and SGCs, with increased nuclear localization and expression in the MOH group. SULT1A1 was localized to the cytoplasm of trigeminal ganglion neurons, not detected in satellite glial cells, and was significantly downregulated in the MOH group.ConclusionOur study showed for the first time that NSAID overuse headache is associated with a robust increase in CGRP, HMGB1, and HIF-1 alpha and reduced SULT1A1 expression in the trigeminal ganglion. Increased nociceptive, inflammatory, and mitochondrial stress signaling in the trigeminal ganglion cells may drive sustained trigeminal nociceptive activity in MOH. Besides, reduced SULT1A1 expression in the trigeminal ganglion suggests reduced capacity of detoxification and catecholamine metabolism in MOH. The role of lipopolysaccharide leakage and systemic nociceptive drive on trigeminal neurons remains to be clarified.