Research advances on the role of glutamate AMPA receptors in the pathogenesis and treatment of migraine: A narrative review

BACKGROUND: Migraine is a prevalent neurological disorder with incompletely understood mechanisms. Glutamate, the primary excitatory neurotransmitter, and its AMPA receptors (AMPARs) have emerged as key players in migraine pathophysiology. OBJECTIVE: This study aimed to synthesize current evidence on the role of AMPA receptors in migraine pathogenesis and to evaluate the therapeutic potential of AMPA receptor antagonists in migraine management. METHODS: This is a narrative review. A literature search was conducted on PubMed using the terms "migraine" AND "glutamate" AND "AMPA receptor." Additional related terms (e.g., "AMPA receptor antagonist," "perampanel," "cortical spreading depression (CSD)," "trigeminovascular system (TVS)," and "central sensitization") were used to broaden the search and capture relevant mechanistic and therapeutic studies. Only "English-language" articles published from inception to 2025 were considered. Relevant preclinical and clinical studies addressing the role of AMPA receptors in migraine pathophysiology (including "CSD," "TVS activation," and "central sensitization") and/or the therapeutic potential of AMPA receptor antagonists, particularly "perampanel," were included. No restrictions were placed on publication type. RESULTS: AMPARs contribute to migraine through multiple pathways. Their role in CSD remains controversial, with conflicting evidence on whether they are essential for CSD initiation and propagation. In contrast, AMPARs clearly facilitate TVS activation by promoting the release of calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP), driving neurogenic inflammation and nociceptive transmission. Moreover, phosphorylation of AMPAR subunits, particularly GluA1 at Ser81 and Ser845, is a critical molecular mechanism underlying central sensitization, leading to allodynia and migraine chronification. Although early AMPAR antagonists, such as BGG492, showed limited clinical efficacy, the selective noncompetitive AMPAR antagonist perampanel has demonstrated anti-migraine potential in preclinical models by inhibiting PACAP and CGRP release and has shown clinical benefit in patients with comorbid epilepsy and migraine. CONCLUSION: AMPA receptors play a pivotal role in TVS activation and central sensitization in migraine. Perampanel is a promising candidate for migraine therapy, but further clinical trials are needed to confirm its efficacy and safety in patients with migraine without epilepsy.