Migraine without aura (MO) is among the most common and debilitating neurological disorders globally, with stress as a significant trigger for attacks. Molecular mechanisms that underlie MO are still not understood. The role of stress sensitivity and transcriptional dysregulation in migraine pathophysiology has become an area of interest, but transcriptomic studies are still limited and inconsistent. Our work aimed to systematically study changes in gene expression related to MO 1) under general interictal conditions and 2) after acute neuroendocrine stress from a citalopram challenge. Under general interictal conditions, no individual genes reached our genome-wide significance thresholds. Gene set enrichment analysis revealed 88 significantly downregulated, replicated biological processes in patients including pathways related to metabolism, immune function, cardiovascular regulation, response to oxidative stress, and hormone signalling. Leading-edge genes such as CYP26B1 and CORIN exhibited substantial and consistent downregulation across time points. In silico binding simulations and machine learning based drug-target prediction models highlighted minimal binding affinity for existing migraine treatments to dysregulated gene products. In contrast, compounds such as probucol and ginsenosides exhibited strong predicted binding to CORIN and additional candidate drugs with potential to modulate key molecular pathways. A pharmacological stress model involving an intravenous administration of citalopram revealed altered neuroendocrine and transcriptional responses in MO patients in parallel to an increase in HPA axis activity at 70 minutes post-infusion. Transcriptomic analysis showed accompanying downregulation of the immune-related genes IKBKGP1 and NKRF and upregulation of carbohydrate metabolism, protein biosynthesis and glycosylation. All in all, molecular patterns support the existence of a maladaptive molecular stress response in migraine and provide a molecular framework for understanding MO as an impaired allostatic regulation disorder. Further investigation based on our findings is warranted to guide future research into mechanism-based therapeutic strategies in the disorder.
