A narrative review of the calcitonin peptide family and associated receptors as migraine targets: Calcitonin gene‐related peptide and beyond

Abstract

Objective To summarize the pharmacology of the calcitonin peptide family of receptors and explore their relationship to migraine and current migraine therapies. Background Therapeutics that dampen calcitonin gene‐related peptide (CGRP) signaling are now in clinical use to prevent or treat migraine. However, CGRP belongs to a broader peptide family, including the peptides amylin and adrenomedullin. Receptors for this family are complex, displaying overlapping pharmacologic profiles. Despite the focus on CGRP and the CGRP receptor in migraine research, recent evidence implicates related peptides and receptors in migraine. Methods This narrative review summarizes literature encompassing the current pharmacologic understanding of the calcitonin peptide family, and the evidence that links specific members of this family to migraine and migraine‐like behaviors. Results Recent work links amylin and adrenomedullin to migraine‐like behavior in rodent models and migraine‐like attacks in individuals with migraine. We collate novel information that suggests females may be more sensitive to amylin and CGRP in the context of migraine‐like behaviors. We report that drugs designed to antagonize the canonical CGRP receptor also antagonize a second CGRP‐responsive receptor and speculate as to whether this influences therapeutic efficacy. We also discuss the specificity of current drugs with regards to CGRP isoforms and how this may influence therapeutic profiles. Lastly, we emphasize that receptors related to, but distinct from, the canonical CGRP receptor may represent underappreciated and novel drug targets. Conclusion Multiple peptides within the calcitonin family have been linked to migraine. The current focus on CGRP and its canonical receptor may be obscuring pathways to further therapeutics. Drug discovery schemes that take a wider view of the receptor family may lead to the development of new anti‐migraine drugs with favorable clinical profiles. We also propose that understanding these related peptides and receptors may improve our interpretation regarding the mechanism of action of current drugs.

Role of adrenomedullin2/ intermedin in pregnancy induced vascular and metabolic adaptation in mice

“…However, physiological role and importance of AM2 in reproduction is not clearly understood due to its structural similarities with its family peptides, CGRP and AM. In addition, AM2 uses a complex receptor system that is shared by CGRP and AM (Roh et al, 2004;Hay et al, 2018;Garelja and Hay. 2022), which limits the use of AM2 antagonist due to its potential cross-reactivity with other family peptides.…”

“…However, the ligand specificity of CLR is dictated by its hetero-dimerization with a group of receptor activity modifying proteins (RAMPs) in such a manner that, RAMP1 and RAMP3 function for CGRP, RAMP2 or RAMP3 can function for AM and all three RAMPs are capable of forming AM2 receptor with CLR (Roh et al, 2004;Takei, et al, 2004). However, majority of the AM2 effects are shown to involve RAMP2 and RAMP3 (Roh et al, 2004;Hay et al, 2018;Garelja and Hay, 2022). These peptides are important for homeostasis in diverse tissues and have similar but distinct physiological effects (Nelson et al, 2000;Roh et al, 2004).…”

Gel-forming antagonist provides a lasting effect on CGRP-induced vasodilation

“…On the other hand, ADM2 is a mild ligand for all three receptors. In addition to CGRP, ADM has been implicated in the regulation of inflammatory heat hyperalgesia, the development of morphine tolerance, and spinal glial activation as well as migraine pain ( Ma et al, 2006 ; Fernandez et al, 2010 ; Wang et al, 2011 ; Zeng et al, 2014 ; Ghanizada et al, 2021 ; Garelja and Hay, 2022 ; Rees et al, 2022 ). Migraine patients infused with ADM developed migraine attacks, suggesting that the ADM-mediated CLR/RAMP2 signaling represents a potential target for migraine treatment ( Ghanizada et al, 2021 ).…”

“…Such candidates would have a high volume of distribution and better access to neuronal targets. In addition, because the CGRP-related adrenomedullin (ADM) peptide, which mainly signals through the CLR/RAMP2 receptor, has been implicated in the development of inflammatory hyperalgesia and migraine pain and because CGRP and ADM receptors are systematically present in human trigeminal ganglia ( Moreno et al, 1999 ), a peptide antagonist that can target multiple CLR/RAMP receptors may have a better potential to alleviate headaches in patients with severe migraine ( Ma et al, 2006 ; Fernandez et al, 2010 ; Wang et al, 2011 ; Zeng et al, 2014 ; Garelja and Hay, 2022 ; Rees et al, 2022 ).…”

Photophobia and migraine outcome during treatment with galcanezumab

“…The neuropeptide calcitonin gene-related peptide (CGRP) is now recognized as a key player in the pathogenesis of migraine (5)(6)(7). CGRP is found in neurons of both the central and the peripheral nervous systems (respectively, CNS and PNS), and its receptors are widespread throughout the body, where it has been implicated in diverse functions (8). In the CNS, the CGRP has been mainly linked to nociceptive signaling, whereas in the periphery, it is the most potent vasodilatory peptide and contributes to neurogenic inflammation.…”