Modulation of HPA axis signaling as a treatment approach for migraine- like behavioral responses caused by repeated stress exposure

Editor’s note: The research described below comes from a recipient of a 2024 MSC Travel Grant supporting travel to the Neurobiology of Stress Workshop 2024. 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 widely recognized as a prevalent trigger for migraines. Despite years of study, the exact mechanism behind stress-induced migraines remains elusive. Glucocorticoids (GCs), released by the adrenal cortex through activation of the hypothalamic-pituitary-adrenal (HPA) axis, play a pivotal role in regulating the body’s adaptive response to acute stress. However, chronic stress can disrupt the balance of GCs, leading to adverse effects such as depression or migraines. Additionally, research suggests that a reduction in stress levels correlates with a decrease in migraine attacks. A deeper comprehension of the role GCs play in stress-induced migraines holds promise for informing the development of new therapeutic strategies for managing migraine.

What is your research hypothesis?

Our proposal suggests that the rapid reduction in glucocorticoid levels following the cessation of stress serves as a trigger for migraine attacks. Therefore, we hypothesize that recurrent exposure to stress, causing fluctuations in GC levels, precipitates migraine occurrences. Inhibiting or reducing glucocorticoid levels induced by stress may serve to prevent this.

What methodology did you use to address your research hypothesis?

This study aims to investigate the role of glucocorticoids and the hypothalamic-pituitary-adrenal (HPA) axis in inducing migraine-like behaviors under stress conditions using a mouse model. Previously, our laboratory established a pre-clinical animal model for stress, where mice undergo repeated restraint stress for 2 hours daily over three consecutive days. This stress induction triggers migraine-like behavioral responses lasting up to 14 days, independent of gender, and sensitizes mice to a low dose of the nitric oxide donor sodium nitroprusside (SNP) for 72 hours. In this research, we utilized this stress mouse model and conducted pharmacological interventions involving a glucocorticoid synthesis inhibitor, corticosterone, adrenocorticotropic hormone (ACTH), and its cleavage product, α-melanocyte stimulating hormone (α-MSH), to explore the impact of the HPA axis on stress-induced migraine mechanisms. Facial hypersensitivity to mechanical stimuli was assessed using the von Frey test to evaluate pain-like behaviors, while spontaneous pain-like behaviors were quantified using the well-established mouse grimace scale (MGS) in a standardized manner. Additionally, the CORT ELISA assay was employed to analyze the effect of restraint stress on serum corticosterone (CORT) levels.

What are the main results of your study?

Administration of metyrapone, a glucocorticoid synthesis inhibitor, effectively mitigated stress-induced migraine-like behaviors in both male and female mice. To replicate the effects of glucocorticoids induced by stress, corticosterone (CORT) was administered, triggering migraine-like behaviors solely in female mice. Furthermore, we delved into the involvement of the HPA axis. ACTH administration ameliorated stress-induced mechanical hypersensitivity compared to the vehicle group. Moreover, treatment with α-MSH, an ACTH cleavage product, reduced mechanical hypersensitivity in stressed mice compared to those receiving vehicle treatment. 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 plays a crucial role in stress-induced migraines, being necessary for their occurrence, and is adequate to induce migraine-like behaviors specifically in female mice. This research illuminates the underlying mechanisms behind stress-triggered migraine attacks and suggests that modulating these hormones could serve as a potential therapeutic avenue for stress-induced migraines.

What are the limitations of your study?

In this study, we applied restraint stress over three consecutive days to elicit migraine-like behaviors in our animal model. Our findings suggest the involvement of stress hormone glucocorticoids in the mechanism underlying stress-induced migraines. However, our study did not explore or offer insights into how the specific method of restraint utilized in the experiment influenced the levels or reactions of stress hormones. This unexamined aspect could be crucial for comprehending the comprehensive impact of stress on the HPA axis and the consequent onset of migraine-like behaviors.

What is the relevance of your study to migraine?

After years of research into the correlation between stress and migraines, the exact mechanisms behind this association remain unclear. The primary goal of our study is to uncover the root cause of how stress triggers migraines. We posit that glucocorticoids play a critical role in the development of stress-induced migraines. Additionally, we introduce a novel hypothesis suggesting that controlling the fluctuations of glucocorticoids and the HPA axis could potentially serve as a new therapeutic strategy for managing migraines.