Effects of olcegepant, sumatriptan, and ibuprofen on migraine-like behavior induced by repetitive restraint stress in mice

Editor’s note: The research described below comes from a recipient of a 2025 MSC Travel Grant supporting travel to the 67th Annual Scientific Meeting of the American Headache Society. These grants reimburse travel expenses for those who have had their abstract for a presentation or poster accepted at a meeting.

By Shiva Nematgorgani, PhD student, University of Texas at Dallas, US.

What is the research gap that your study addresses?

The research gap addressed by this study is the lack of validation of the early post-stress phase in a mouse model of stress-induced migraine-like behaviors for its responsiveness to migraine therapeutics. Prior studies using the repetitive stress exposure model had not investigated how acute migraine treatments affect hypersensitivity and facial grimace responses following stress.

This study demonstrates that these therapeutics attenuate stress-induced hypersensitivity, with olcegepant showing a stronger effect, implicating CGRP signaling. And, by revealing that ibuprofen reduces mechanical hypersensitivity but not grimace responses, the study suggests that grimace may capture negative affect rather than just pain.

What is your research hypothesis?

The research hypothesis of this study is that ibuprofen, sumatriptan, and olcegepant will attenuate stress-induced facial hypersensitivity and hyperalgesic priming in a mouse model of migraine-like behaviors, with differential effects on mechanical hypersensitivity and facial grimace responses.

What methodology did you use to address your research hypothesis?

Female CD1 mice aged 6-8 weeks were exposed to 2 hours of restraint stress for 3 consecutive days. Twenty-four hours after the final day of restraint stress, the first administration of sumatriptan (0.6 mg/kg, subcutaneous) and olcegepant (1 mg/kg, intraperitoneal) was performed. These injections were repeated for sumatriptan on Day 3, while olcegepant was injected on Day 2, and Day 3. Additionally, Ibuprofen (200 mg/kg, intraperitoneal) was administered 24 hours post-stress.

Periorbital withdrawal thresholds using von Frey filaments and facial grimace scores were measured on Day 1, 3, 5, 7, 10, and 14 following stress.

These measurements were also performed at 1, 3, and 5 hours after each drug injection.

On Day 14, animals received an injection of sodium nitroprusside (SNP, 0.1 mg/kg). Von Frey testing and facial grimace scoring were conducted 1 hour, 3 hours, and on Days 1 and 2 after SNP injection. Data were analyzed using Prism 10 software (GraphPad Software, San Diego, CA, USA) with a two-way ANOVA, followed by Bonferroni post hoc analyses.

What are the main results of your study?

Repeated restraint stress in mice induced persistent facial hypersensitivity and elevated grimace scores, modeling migraine-like behaviors. Ibuprofen, sumatriptan, and olcegepant reduced hypersensitivity, with olcegepant showing the strongest effect, significantly lowering both hypersensitivity and grimace scores. Ibuprofen and sumatriptan reduced hypersensitivity but not grimace scores. On Day 14, a subthreshold SNP dose triggered primed hypersensitivity, attenuated only by olcegepant. These findings validate the model for testing migraine therapeutics and highlight CGRP’s role in stress-induced migraine and the distinct pain and affective components captured by von Frey and grimace measures.

What conclusions did you reach based on your results?

We showed that repeated restraint stress in mice can cause migraine-like behaviors that are responsive to several migraine therapeutics. These data further validate this model as being translationally relevant for testing migraine therapeutics and they provide insight into the mechanisms by which stress causes behavioral features consistent with migraine.

What are the limitations of your study?

Only female CD1 mice were used in this study. Given sex differences in stress and migraine responses, the effects observed may not generalize to male mice.

Additionally, the interpretation that facial grimace scores reflect negative affect rather than pain alone remains speculative. This assumption requires further validation through complementary behavioral or pharmacological studies, which we are currently pursuing.

What is the relevance of your study to migraine?

This study is relevant to migraine research as it validates a mouse model of stress-induced migraine-like behaviors, addressing the critical link between stress – a major migraine trigger reported by 80% of patients – and migraine pathophysiology. The differential effects of ibuprofen, sumatriptan, and olcegepant on facial grimace versus hypersensitivity suggest distinct pain and affective components, offering insights into comprehensive migraine treatment. The model’s translational relevance supports its use for testing novel therapeutics, advancing migraine management strategies.