Dysregulation of the peripheral glutamatergic system: A key player in migraine pathogenesis?

BACKGROUND: Although the role of glutamate in migraine pathogenesis remains uncertain, there has been significant interest in the development of drug candidates that target glutamate receptors. Activation of trigeminovascular afferent fibers is now recognized as a crucial step to the onset of a migraine episode. New evidence suggests a dysfunction in peripheral glutamate regulation may play a role in this process. OBJECTIVE: To provide a narrative review of the role of peripheral glutamate dysfunction in migraine. METHOD: A review of recent literature from neurobiological, pharmacological and genomic studies was conducted to support peripheral glutamate dysfunction as a potential element in migraine pathogenesis. RESULTS: Studies in rats suggest that elevated blood glutamate mechanically sensitizes trigeminal afferent fibers and stimulates the release of calcitonin-gene related peptide and other neuropeptides to promote and maintain neurogenic inflammation. These effects may be driven by upregulation of glutamate receptors, and modifications to reuptake and metabolic pathways of glutamate. Furthermore, genome wide association studies have found polymorphisms in glutamate receptor and transporter genes that are associated with migraine. CONCLUSION: The role of peripheral glutamate signalling in the onset and maintenance of migraine is not completely elucidated and future studies are still needed to confirm its role in migraine pathogenesis.