Future targets for migraine treatment beyond CGRP

• Published in: Journal of headache and pain Vol. 24; no. 1; p. 76
• Main Authors: Al-Hassany, Linda, Boucherie, Deirdre M., Creeney, Hannah, van Drie, Ruben W. A., Farham, Fatemeh, Favaretto, Silvia, Gollion, Cédric, Grangeon, Lou, Lyons, Hannah, Marschollek, Karol, Onan, Dilara, Pensato, Umberto, Stanyer, Emily, Waliszewska-Prosół, Marta, Wiels, Wietse, Chen, Hui Zhou, Amin, Faisal Mohammad
• Format: Journal Article
• Language: English
• Published: Milan Springer Milan 28.06.2023; Springer Nature B.V; BMC
• Subjects: Acidity; Adrenomedullin; Adrenomedullin - metabolism; Amylin; Calcitonin; Calcitonin gene-related peptide; Calcitonin Gene-Related Peptide - metabolism; Calcium channels; Headache; Headache Disorders; Headaches; Hot topics in headache and pain from the EHF-SAS; Humans; Internal Medicine; Islet Amyloid Polypeptide - metabolism; Medicine; Medicine & Public Health; Metabotropic receptors; Migraine; Migraine Disorders - drug therapy; Neurology; Nitric oxide; Non-CGRP targets; PAC1 protein; Pain Medicine; Peptides; Pituitary adenylate cyclase-activating polypeptide; Pituitary Adenylate Cyclase-Activating Polypeptide - metabolism; Potassium; Potassium channels; Receptors, Calcitonin Gene-Related Peptide; Review; Sodium channels; Therapeutic targets; Transient receptor potential proteins; Vasoactive agents; Vasoactive intestinal peptide; Vasoactive intestinal polypeptide; Pituitary adenylate cyclase-activating polypeptide; Migraine; Vasoactive intestinal polypeptide; Nitric oxide; Non-CGRP targets; Amylin; Adrenomedullin; Ion channels; Phosphodiesterases
• ISSN: 1129-2377; 1129-2369; 1129-2377
• DOI: 10.1186/s10194-023-01567-4

Background Migraine is a disabling and chronic neurovascular headache disorder. Trigeminal vascular activation and release of calcitonin gene-related peptide (CGRP) play a pivotal role in the pathogenesis of migraine. This knowledge has led to the development of CGRP(-receptor) therapies. Yet, a substantial proportion of patients do not respond to these treatments. Therefore, alternative targets for future therapies are warranted. The current narrative review provides a comprehensive overview of the pathophysiological role of these possible non-CGRP targets in migraine. Findings We covered targets of the metabotropic receptors (pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP), amylin, and adrenomedullin), intracellular targets (nitric oxide (NO), phosphodiesterase-3 (PDE3) and -5 (PDE5)), and ion channels (potassium, calcium, transient receptor potential (TRP), and acid-sensing ion channels (ASIC)). The majority of non-CGRP targets were able to induce migraine-like attacks, except for (i) calcium channels, as it is not yet possible to directly target channels to elucidate their precise involvement in migraine; (ii) TRP channels, activation of which can induce non-migraine headache; and (iii) ASICs, as their potential in inducing migraine attacks has not been investigated thus far. Drugs that target its receptors exist for PACAP, NO, and the potassium, TRP, and ASIC channels. No selective drugs exist for the other targets, however, some existing (migraine) treatments appear to indirectly antagonize responses to amylin, adrenomedullin, and calcium channels. Drugs against PACAP, NO, potassium channels, TRP channels, and only a PAC 1 antibody have been tested for migraine treatment, albeit with ambiguous results. Conclusion While current research on these non-CGRP drug targets has not yet led to the development of efficacious therapies, human provocation studies using these targets have provided valuable insight into underlying mechanisms of migraine headaches and auras. Further studies are needed on these alternative therapies in non-responders of CGRP(-receptor) targeted therapies with the ultimate aim to pave the way towards a headache-free future for all migraine patients.