The Potential Role of Glutamate Receptors and their Antagonists or Modulators in Migraine Therapy

Background: Glutamate is implicated in playing a crucial role in modulating the complex pathophysiological mechanisms of migraines, including central or peripheral sensitization, cortical spreading depression, and pain transmission. With expanding knowledge over the last three decades, glutamate receptors have become focal points in neurological drug research. Altered plasma glutamate levels during migraines suggest a potential avenue for effective therapies targeting glutamate reduction. Furthermore, glutamate is believed to play a vital role in modulating the complex pathophysiological mechanisms underlying migraines. Objective: This study aims to provide an overview of the ionotropic glutamate receptor antagonists (NMDA, AMPA, and Kainate receptors) and metabotropic glutamate receptors in the context of migraines. We explore the advantages and disadvantages of these receptor modulators as alternative treatments, considering efficacy, tolerability, and safety. Methods: We conducted comprehensive online searches across various electronic databases, with a primary focus on PubMed and clinicaltrials.gov, to gather the latest treatment approaches and emerging concepts. Results: A total of 371 articles were identified from PubMed, along with 69 articles from clinicaltrials. gov. After refinement, 113 articles were included. We summarize seven different medications currently in clinical practice for migraines and highlight six items for migraine therapy in preclinical trials and their potential value. Conclusion: It's crucial to note that these agents pose certain challenges in specific drug research due to their intricate influence and mechanisms of action within multiple neuronal pathways. Therefore, further studies are warranted to elucidate more specific glutamatergic signaling pathways for migraine therapy while minimizing interference with normal neuronal functions.