Role of Glucocorticoids and Upstream Hormones in a Mouse Migraine Model Caused by Repeated Exposure to Stress

Editor’s note: The research described below comes from a recipient of a 2023 MSC Travel Grant supporting travel to the 65th 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 Ya-Yu Hu, PhD student, University of Texas at Dallas, US.

What is the research gap that your study addresses?

Stress is identified as a common trigger for migraine. The mechanism behind stress-induced migraine has been studied for years but remains unknown. Glucocorticoids (GCs) are released by the adrenal cortex through the activation of the hypothalamic-pituitary-adrenal (HPA) axis and regulate adaptive responses upon exposure to acute stress, while chronic stress induces GC fluctuation, contributing to maladaptive effects such as anxiety, depression, or migraine. Additionally, previous studies have shown that a decline in stress is associated with migraine attacks. Better understanding of the role of GCs in stress-induced migraine could inform development of migraine treatments.

What is your research hypothesis?

We hypothesize that repeated exposure to stress, and the resulting fluctuations in GC levels, leads to migraine attacks. Normalization of changes in GC levels induced by stress can prevent or reverse migraine attacks.

What methodology did you use to address your research hypothesis?

The objective of this study was to examine the involvement of glucocorticoids and the HPA axis in stress-induced migraine-like behaviors, using a mouse model. Our laboratory has previously developed a pre-clinical animal model where mice are exposed to repeated restraint stress for 2 hours per day over 3 consecutive days. This stress induction leads to migraine-like behavioral responses lasting for a period of 14 days, regardless of the gender of the animals. Additionally, it primes mice to a low dose of a nitric oxide donor called sodium nitroprusside (SNP) for a duration of 72 hours. In this study, we used this stress mouse model and pharmacological manipulations including a glucocorticoid synthesis inhibitor, corticosterone (CORT), adrenocorticotropic hormone (ACTH), and its cleavage product α-melanocyte-stimulating hormone (α-MSH) to examine the influence of the HPA axis on the mechanisms of stress-induced migraine behavior. To evaluate pain-like behaviors, we used the von Frey test to measure facial hypersensitivity to mechanical stimuli. Additionally, we utilized the mouse grimace scale (MGS), a well-established behavioral coding system, to evaluate spontaneous pain-like behaviors in a standardized manner. Furthermore, we used a CORT ELISA assay to investigate the impact of restraint stress on serum CORT levels.

What are the main results of your study?

Administration of metyrapone, a glucocorticoid synthesis inhibitor, effectively blocked stress-induced migraine-like behaviors in both male and female mice. To mimic the GC effect induced by stress, CORT was injected and induced migraine-like behaviors only in female mice. We further investigated the involvement of the HPA axis. ACTH administration alleviated stress-induced mechanical hypersensitivity compared to the vehicle group. Additionally, treatment with α-MSH, a cleavage product of ACTH, reduced mechanical hypersensitivity in stressed mice, compared to those treated with vehicle. Serum CORT levels peaked 30 minutes after stress or CORT injections and returned to baseline within 24 hours.

What conclusions did you reach based on your results?

CORT is necessary for stress-induced migraine-like behavior, while it is only sufficient to produce migraine-like behaviors in female mice. The study identifies potential mechanisms contributing to stress-induced migraine attacks, provides information about the modulation of these hormones, and may lead to therapeutic approaches for migraine attacks caused by stress.

What are the limitations of your study?

In this study, we used restraint stress for 3 consecutive days to induce migraine-like behaviors in an animal model. However, this study did not investigate or provide information on how the method of restraint employed in the experiment affected the levels or responses of stress hormones. This missing analysis could potentially be relevant in understanding the overall effects of stress on the HPA axis and the subsequent development of migraine-like behaviors.

What is the relevance of your study to migraine?

Despite decades of research linking stress and migraine, the underlying mechanisms of this relationship remain elusive and not fully understood. The objective of this study was to uncover the underlying cause of how stress acts as a trigger for migraines.  We show that GCs play crucial roles in the development of stress-induced migraine behaviors in mice. Furthermore, we propose an innovative hypothesis that suggests modulation of the fluctuations of GCs and the HPA axis could potentially be a novel therapeutic strategy for managing migraine.