The role of HPA signaling, the melanocortin system, and BLA dendrite changes in repeated stress-induced migraine-like behaviors

The 2024 MSC Emerging Science Contest for Early-Career Investigators took place on December 9, 2024. Below is a written summary of one of the presentations from the contest. (A recording of the event is available here).

Category: Migraine

Winner: Ya-Yu Hu, UT Dallas

Title: The role of HPA signaling, the melanocortin system, and BLA dendrite changes in repeated stress-induced migraine-like behaviors.

Hypothesis, methodology, findings and conclusions
Stress is a well-known trigger for migraines, but the biological pathways connecting stress to migraine onset remain unclear. To investigate this, we used a stress-induced migraine preclinical animal model, assessing pain sensitivity through the von Frey test and Grimace score. Our study focused on the role of the HPA axis in stress-induced migraines, using metyrapone to block corticosterone (CORT) production.

We found that metyrapone reduced migraine-like symptoms, indicating that CORT plays a significant role. However, the effect could also involve increased ACTH, a hormone that stimulates the adrenal glands. Administration of ACTH after stress alleviated symptoms in both male and female mice, while treatment with THIQ, a melanocortin 4 receptor agonist, also reduced symptoms.

We also investigated the impact of stress on basolateral amygdala (BLA) dendritic changes using Golgi staining. The results showed that repetitive stress increased dendrite length and the number of dendritic spines in females at 72 hours post-stress. These results suggest that both CORT and ACTH contribute to stress-induced migraines, with ACTH acting independently of CORT in males, but partially relying on CORT in females. This study offers valuable insights into the mechanisms linking stress to migraines and could inform the development of more targeted treatments for stress-related migraines. These findings have the potential for rapid translation into clinical trials, offering a novel therapeutic approach for migraine management.

Implications for understanding migraine disease and/or its comorbidities, or how the research holds promise as a new avenue of future migraine study.
The implications of this research for understanding migraine disease are significant, particularly in how stress contributes to migraine onset and exacerbation. By identifying the role of the HPA axis and key hormones like CORT and ACTH in stress-induced migraine-like behaviors, this study provides a deeper understanding of the biological mechanisms underlying migraines, especially in individuals whose migraines are triggered or worsened by stress. Furthermore, the findings suggest that targeting specific components of the HPA axis or melanocortin signaling could offer new therapeutic strategies for managing stress-related migraines. This research also opens up new avenues for future studies exploring how hormonal regulation and stress responses contribute to the development of comorbidities often seen with migraines, such as anxiety and depression. Ultimately, the insights gained from this study could lead to more personalized and effective treatments for migraine patients, particularly those with stress-induced migraine attacks.