2023 MSC Poster Contest Presentation: Modulation of HPA axis signaling as a treatment approach for migraine-like behavioral responses caused by repeated stress exposure

The 2023 MSC Emerging Science Contest for Early-Career Investigators took place on December 13, 2023. Below is a written summary of one of the presentations from the contest. Read about other presentations from the event in our Early-Career Science Library.

Category: Special sensory systems/co-morbidities

Winner: Ya-Yu Hu, PhD student, UT Dallas, US

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

Hypothesis, methodology, findings and conclusions.

Stress is one of the most common precipitating factors in migraine and is a trigger in nearly 70% of migraine patients. The nervous system responds to stressors by activating neuroendocrine systems, the hypothalamic-pituitary-adrenal (HPA) axis, and by releasing glucocorticoids, which produces behavior change and maintains homeostasis. Although it has adaptive value, migraine headache may be an adverse consequence of glucocorticoid response.

Our lab previously has shown that repeated physical restraint stress in mice for two hours each day for three consecutive days can evoke migraine-like behavioral responses as well as priming to the nitric oxide donor sodium nitroprusside (SNP). CD-1 male and female mice were used to investigate the effect of GCs, and their upstream hormones including ACTH and α-MSH, on stress-induced migraine-like responses in mice. Facial mechanical hypersensitivity was evaluated by von Frey testing and grimace score assessed the presence of non-evoked pain.

In this study, we used this stress model to test whether corticosterone (CORT), ACTH, and α-MSH contribute to these effects. To test whether CORT contributes to the effects, we gave subcutaneous injections of metyrapone, an inhibitor of glucocorticoid synthesis, or mifepristone, a glucocorticoid receptor antagonist, 40 minutes prior to each restraint stress exposure. Our findings indicate that the administration of metyrapone blocked the migraine-like behaviors induced by stress. This outcome suggests a pronounced reliance on CORT synthesis for the behavioral responses but a lack of CORT also causes increased compensatory release of ACTH. To test whether upstream ACTH or its breakdown products contribute to these effects, stressed animals were treated with either ACTH or α-MSH post-stress. Both caused a reduction in mechanical hypersensitivity and grimace scores during the post-stress phase as well as the priming phase. To determine a potential receptor mediating these effects, we administered THIQ, a melanocortin 4 receptor (MC4R) agonist, to animals after stress. THIQ alleviated stress-induced migraine-like behaviors in female mice. We also measured serum CORT levels in control and stress conditions in both male and female mice.

Our findings reveal the essential role of changes in glucocorticoid levels in stress-induced behavioral responses in both male and female mice. Furthermore, an increase of ACTH levels, along with the subsequent cleavage product α-MSH, following stress exposure can also influence the hypersensitivity induced by stress. This study contributes to our understanding of the intricate relationship between stress and migraine, potentially providing a novel therapeutic approach for treatment of stress-induced migraine attacks.

Implications for understanding migraine disease and/or its comorbidities, or how the research holds promise as a new avenue of future migraine study.

Previous studies have shown that migraine attacks often manifest during the relaxation phase following the cessation of stress. This implies that the drop from an elevated stress state may be the trigger of migraine attacks, possibly due to the ability of stress hormones to produce rapid structural and functional effects on the nervous system. Our study demonstrates that glucocorticoids are essential and important for stress-induced migraine-like behaviors. Moreover, in addition to glucocorticoids as well as their upstream hormones ACTH/α-MSH, the MC4R also contributes to the sensitizing effects of repeated stress. This suggests that modulation of these hormones may be a therapeutic approach for migraine attacks caused by stress. In this study, we used pharmacological tools that are FDA approved, such as metyrapone and mifepristone, to regulate glucocorticoids and their receptors, allowing rapid translation of findings into human studies. Administration of metyrapone or mifepristone to inhibit the actions of glucocorticoids induced by stress or post-stress administration of ACTH, α-MSH, or even THIQ, offer possible new therapeutic approaches for migraine.

There are many comorbidities associated with migraine. According to a recent review, the prevalence of anxiety in individuals with migraine is approximately four times higher than in those without migraine. The connection between anxiety disorders and migraine headaches appears to be reciprocal, with migraine potentially triggering anxiety and anxiety predisposing individuals to migraine. Beyond anxiety, migraine also elevates the likelihood of experiencing depression or post-traumatic stress disorder (PTSD). Those with migraine are four times more prone to PTSD compared to individuals without headache. This reciprocal influence implies that specific factors may contribute to the susceptibility to these disorders. While the relationship between migraine and other disorders remains unclear, several studies have identified shared pathophysiological features. For instance, dysregulation of the HPA axis has been observed in both PTSD and anxiety. Additionally, certain proinflammatory cytokines implicated in migraine are found to be elevated in individuals with PTSD. Our study not only emphasizes the pivotal role of the HPA axis and glucocorticoids in the mechanism of stress-induced migraine but also proposes the use of an animal model to explore the overlap between migraine and other disorders.