Acute neuroendocrine challenge elicits enhanced cortisol response and parallel transcriptomic changes in patients with migraine

Introduction: Migraine is a neurological disorder with recurrent attacks characterized by headaches and sensitivity to stimuli. Stress is a significant trigger for attacks; however, molecular mechanisms of the connection are poorly understood. Objectives: To better characterize such mechanisms, we performed a placebo-controlled, double-blind crossover study with 51 participants (21 patients with migraine without aura and 30 healthy controls). Methods: Participants received a low-dose citalopram- or placebo challenge on 2 separate days. Prechallenge and postchallenge assessment of cortisol concentrations and transcriptomic changes using RNA-seq was performed from whole blood samples. Analysis of an accidental attack following the citalopram challenge was also conducted. Results: Neuroendocrine challenge elicited elevated cortisol concentrations at 30 ( P -value = 0.1355) and 70 minutes ( P -value = 0.07292) postchallenge in patients with migraine compared with controls. Gene expression analysis showed 10 differentially expressed genes (2 down- and 8 upregulated, P -value ≤ 0.005) and 10 dysregulated gene sets ( P -value ≤ 0.005). Among them, dysregulated IKBKGP1 and NKRF genes and upregulated protein synthesis and translation, carbohydrate metabolism, and, attack-related, glycosylation can be highlighted. Conclusion: Patients with migraine without aura showed an enhanced cortisol response to a neuroendocrine challenge. This was accompanied by a probable suppression of NF κ B activity through dysregulation of NKRF and an altered immune function. Upregulated carbohydrate metabolism may reflect the elevated cortisol concentrations' stimulating effects on endothelial glycocalyx, playing a role in NO-induced vasodilation, a trigger for migraine attacks. The results suggest the elevated cortisol response may trigger migraine attacks through altered glycocalyx and immune functions.