Dipyrone overuse causes sex-dependent trigeminal sensitization in female rats, a CGRP-mediated headache model | Research

The takeaway

Chronic dipyrone treatment induced latent trigeminal sensitization selectively in female rats (revealed by light exposure), without changing CGRP plasma levels, in a CGRP injection-based medication overuse headache model.

Female-only sensitization
Chronic dipyrone induced latent trigeminal sensitization selectively in female rats, mirroring the clinical female predominance of medication overuse headache

What the researchers found

Acute dipyrone reduced CGRP-induced allodynia in both sexes. Chronic dipyrone (30 days): latent sensitization in females only (revealed by bright light). No effect on paw threshold, locomotion, or plasma CGRP. Sex-dependent vulnerability.

Why it matters

MOH affects millions worldwide, predominantly women. This provides the first preclinical evidence that a widely used analgesic causes sex-specific trigeminal sensitization, supporting the clinical observation of female vulnerability to MOH.

How the study worked

Rat model: trigeminal CGRP injection (0.1 nmol) for acute testing. Chronic: dipyrone 120 mg/kg 2x/day for 30 days. Periorbital mechanical threshold, bright light challenge, hindpaw assessment, locomotion, plasma CGRP.

What this study cannot tell us

Animal model may not fully replicate human MOH. Single analgesic tested. CGRP plasma may not reflect brain levels. Mechanism of sex difference not elucidated.

How to read the evidence

Well-designed preclinical study with appropriate controls and sex comparison. First to demonstrate sex-dependent dipyrone-induced MOH in CGRP model.

When this study was published

Published in 2025.

The bigger picture

Understanding sex differences in MOH development could guide sex-specific treatment recommendations and prevention strategies. The CGRP-based model validates the role of neuropeptides in medication overuse headache pathophysiology.

Questions still open

Why are females more susceptible to dipyrone-induced sensitization?
Would anti-CGRP drugs prevent MOH development?
Does this model apply to other common analgesics like ibuprofen?

Common questions

Can taking too many painkillers cause headaches?

Yes—medication overuse headache (MOH) affects people who use analgesics too frequently. This study used a CGRP-based model to show that chronic dipyrone use specifically sensitizes the trigeminal pain system in females, suggesting women may be more vulnerable to developing MOH.

Why are women more affected by medication overuse headache?

This study provides a biological explanation: chronic analgesic use caused trigeminal nerve sensitization only in female rats. While the exact mechanism is unknown, hormonal differences and sex-specific pain processing pathways likely contribute to this vulnerability.

Read the original research

Dipyrone induces sex-dependent latent sensitization in a preclinical model of medication overuse headache.

European journal of pharmacology, 1006, 178173

View on PubMed ↗Publisher’s paper ↗

Citation

Spagnol, Fernanddo José; Zortea, Julia Maria; Gomes, Larissa Cieslinsky; da Luz, Fernanda Mariano Ribeiro; Baggio, Darciane Favero; Lejeune, Vanessa Bordenowsky Pereira; Ferreira, Luiz Eduardo Nunes; Kopruszinski, Caroline Machado; Chichorro, Juliana Geremias. (2025). Dipyrone induces sex-dependent latent sensitization in a preclinical model of medication overuse headache.. European journal of pharmacology, 1006, 178173. https://doi.org/10.1016/j.ejphar.2025.178173