The evolving landscape of migraine pathophysiology

Migraine is a complex neurological disorder charac-terised by recurrent headaches, often accompanied by a range of sensory and autonomic symptoms. While vascular theories once dominated, recent evidence highlights the predominant role of the central nervous system in originating migraine pain. The current consensus emphasises the central roles of trigemino-vascular pathways, brainstem regions, and diencephalic nuclei in migraine pathogenesis. Key neurotransmitters, including monoamines such as serotonin, dopamine, and norepinephrine, as well as neuropeptides such as calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP), are pivotal in mediating pain transmission within these pathways.
Premonitory phase symptoms like food cravings, yawning, and mood changes are linked to central nervous system alterations and precede the headache phase. The aura phase, characterized by gradual onset symptoms such as scotomas and paraesthesia, is attributed to cortical spreading depression, a wave of self-propagating neuronal depolarisation followed by transient cortical hypo-perfusion, underscoring its neuronal basis.
The transition to chronic migraine involves dys-function in top-down pain modulation and sen-sitization of the trigeminal system, leading to central sensitization. Peripheral sensitization and molecular mechanisms involving CGRP, Serotonin (5-HT), and PACAP further contribute to migraine chronification. Additionally, oestrogen modulates pain pathways through its effects on the  µ-opioid system and neurotransmitters such as serotonin as well as its regulatory action on CGRP. This multifaceted interplay of circuits, neuropeptides, and hormonal influences determines the complex pathophysiology of migraine, providing avenues for targeted therapeutic interventions.