NSAID overuse headache involves increased CGRP, HMGB1, and HIF-1α with decreased detoxification in trigeminal ganglion | Research

The takeaway

Chronic NSAID overuse in female rats increased trigeminal ganglion CGRP, HMGB1 (cytoplasmic translocation), and HIF-1α (nuclear localization) while decreasing SULT1A1—revealing inflammatory, hypoxic, and detoxification mechanisms in medication overuse headache.

Four MOH mechanisms revealed
Beyond CGRP, NSAID overuse headache involves HMGB1 inflammation, HIF-1α hypoxic stress, and SULT1A1 detoxification failure in the trigeminal ganglion

What the researchers found

↑CGRP neurons + protein. HMGB1: ↑cytoplasmic translocation (neurons + SGCs). HIF-1α: ↑nuclear localization (neurons + SGCs). SULT1A1: significantly ↓ (neurons only, not SGCs). Female rats. Piroxicam MOH model. First description of HMGB1/HIF-1α changes in MOH.

Why it matters

MOH affects 1-2% of the population. Understanding its molecular basis through CGRP, inflammation (HMGB1), hypoxia (HIF-1α), and detoxification (SULT1A1) reveals new therapeutic targets beyond simply stopping the offending medication.

How the study worked

Female Sprague Dawley rats. Oral piroxicam MOH induction. Periorbital mechanical thresholds + nociceptive behaviors (metestrus/diestrus phases). TG immunohistochemistry + Western blot for CGRP, HMGB1, HIF-1α, SULT1A1.

What this study cannot tell us

Rat model. Female-only (relevant for female-predominant MOH). Single NSAID tested. Mechanisms are correlative. LPS/gut permeability role not clarified.

How to read the evidence

First preclinical characterization of HMGB1/HIF-1α/SULT1A1 in MOH. Novel findings.

When this study was published

Published in 2025.

The bigger picture

MOH is more than just CGRP elevation—it involves inflammatory danger signals (HMGB1), cellular stress (HIF-1α), and impaired detoxification (SULT1A1). Multi-target therapy addressing all four mechanisms may be needed.

Questions still open

Could HMGB1 inhibitors treat MOH?
Does HIF-1α stabilization contribute to pain chronification?
Would restoring SULT1A1 activity help prevent MOH?

Common questions

What happens in the brain during medication overuse headache?

This study found 4 molecular changes in the trigeminal pain system: increased CGRP (pain signaling), increased HMGB1 (inflammation), increased HIF-1α (cellular stress), and decreased SULT1A1 (reduced ability to detoxify pain substances). All of these together drive the chronic pain of MOH.

Why is MOH more common in women?

This study specifically used female rats for relevance to the female predominance of MOH. The hormonal cycle (estrus phase) was controlled during testing. The molecular changes in CGRP, inflammation, and detoxification pathways may interact with female-specific factors to increase MOH susceptibility.

Read the original research

Altered expressions of CGRP, SULT1A1, HMGB1, and HIF-1α in the trigeminal ganglion in medication overuse headache in female rats.

The journal of headache and pain, 26(1), 221

View on PubMed ↗Publisher’s paper ↗

Citation

Topa, Elif Gulcicek Abbasoglu; Vuralli, Doga; Usta, Duygu Deniz; Calikusu, Aysen; Yigman, Zeynep; Bolay, Hayrunnisa. (2025). Altered expressions of CGRP, SULT1A1, HMGB1, and HIF-1α in the trigeminal ganglion in medication overuse headache in female rats.. The journal of headache and pain, 26(1), 221. https://doi.org/10.1186/s10194-025-02191-0