Inflammation in Migraine Headaches: From Pathophysiological Mechanisms to Emerging Therapeutic Targets-An Updated Review

Abstract

Background: Migraine is a highly prevalent neurological disorder and one of the leading causes of disability worldwide. Increasing evidence indicates that inflammation and neuroinflammation play fundamental roles in migraine pathogenesis through complex interactions involving immune mediators, neurotransmitters, and neurovascular signaling pathways. These inflammatory mechanisms also contribute to the high prevalence of psychiatric comorbidities, particularly depression, thereby increasing disease burden and complicating clinical management. Aim: This review aims to comprehensively examine the role of inflammation and neuroinflammation in migraine pathophysiology, with particular emphasis on inflammatory cytokines, nitric oxide, glutamate, calcitonin gene-related peptide (CGRP), and their therapeutic implications. Methods: A narrative review of the current literature was conducted using published experimental, clinical, and epidemiological studies focusing on migraine pathogenesis, inflammatory biomarkers, neurotransmitter dysregulation, neuroimmune mechanisms, and emerging targeted therapies. Results: Evidence demonstrates that activation of the trigeminovascular system, microglial activation, and neurogenic inflammation initiate the release of pro-inflammatory cytokines, nitric oxide, glutamate, and CGRP, resulting in cortical spreading depression, peripheral and central sensitization, and persistent nociceptive signaling. Dysregulation of these inflammatory pathways contributes to migraine chronification, increased pain sensitivity, and the frequent coexistence of depression. Recent therapeutic advances targeting CGRP signaling and inflammatory mediators have significantly improved migraine prevention and treatment, although considerable interindividual variability in treatment response remains. Conclusion: Inflammation represents a central mechanism underlying migraine initiation, progression, and chronicity. A better understanding of neuroimmune interactions and inflammatory signaling pathways may facilitate the development of personalized therapeutic strategies and novel disease-modifying interventions that improve clinical outcomes in patients with migraine.