ArticleThe journal of headache and pain2025
Altered expressions of CGRP, SULT1A1, HMGB1, and HIF-1α in the trigeminal ganglion in medication overuse headache in female rats.
Article in The journal of headache and pain, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Mechanistic investigation of HMGB1 in an in vitro model of the trigeminovascular system under migraine-like conditions.The journal of headache and pain · 2026Article
- Involvement of peripheral and central sensitization in prolonged mechanical allodynia of the tongue in a rat.Odontology · 2026Article
- Temporal regulation of macrophage polarization by abnormally innervated CGRP + Sensory nerves following spinal cord injury.Cellular and molecular life sciences : CMLS · 2026Review
- Spreading depolarization activates the cGAS-STING pathway and drives cranial nociception: therapeutic potential of STING modulation.The journal of headache and pain · 2026Article
- Botulinum toxin type E alleviates trigeminal neuropathic pain via modulation of the HIF-1α-NLRP3 pathway.Frontiers in toxicology · 2026Article
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Authors and funding
6 authors.
Funding
Abstract
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-1α) 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-1α, 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-1α 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-1α 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.
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