Post-stress modulation of the HPA and melanocortin systems alleviates migraine-like behaviors in mice

Background: Stress is a major trigger for migraine attacks. Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, releasing glucocorticoids (GCs) to maintain homeostasis, and migraine attacks may occur as an adverse effect of this response. We previously demonstrated in a mouse model that inhibiting corticosterone (CORT) synthesis by administering metyrapone before stress prevented stress-induced migraine-like behaviors. Given the unpredictable nature of stressors and their onset or termination, it is critical to better understand the adaptive and maladaptive effects of the HPA stress response. Here, we aimed to evaluate the effects of HPA axis modulation following the end of stress exposure. Methods: Repeated stress induces migraine-like behaviors and priming to sodium nitroprusside (SNP) in mice. Metyrapone (to inhibit CORT synthesis), CORT (to evaluate its effects after exogenous administration), and adrenocorticotropic hormone (ACTH) (to test the effects of a hormone upstream to CORT) were administered post-stress. Additionally, α-melanocyte-stimulating hormone (α-MSH, an ACTH cleavage product) and tetrahydroisoquinoline (THIQ), a melanocortin 4 receptor (MC4R) agonist, were administered to examine melanocortin receptor involvement. Facial hypersensitivity was assessed via von Frey testing and grimace scoring was used to evaluate non-evoked pain. Serum CORT levels were measured in both control and stressed mice following ACTH administration. Results: We examined post-stress HPA axis modulation on stress-induced facial hypersensitivity. Metyrapone reduced acute-phase hypersensitivity and reduced priming to SNP, suggesting sustained synthesis of CORT after stress plays a role in development of migraine-like behavior. Surprisingly, both CORT and ACTH treatments at 1- and 24-h post-stress alleviated stress-induced behaviors and priming. To determine if ACTH effects were mediated by an elevation in circulating CORT, metyrapone was administered before the ACTH injection. Metyrapone increased the ACTH reversal of stress effects on facial hypersensitivity. Furthermore, post-stress ACTH injections significantly increased serum CORT levels within 30 min. In addition to ACTH effects on CORT levels, ACTH effects could be mediated by the melanocortin system. Post-stress administration of α-MSH or the MC4R agonist THIQ, reduced migraine-like behaviors. Conclusions: There is a complex relationship between stress, the HPA axis, and melanocortin signaling, in the effects of repeated stress exposure on migraine-like behaviors. In the early post-stress response phase, there are contributions from both CORT and MC4R signaling in the maintenance of behavioral effects. These findings suggest that targeting the HPA axis and MC4R after stress may be a potential therapeutic approach for stress-induced migraine attacks.