Abstract

Migraine is one of the most common of neurological disorders with a global prevalence of up to 15%. One in five migraineurs have frequent episodic or chronic migraine requiring prophylactic treatment. In recent years, specific pharmaceutical treatments targeting calcitonin gene-related peptide (CGRP) signalling molecules have provided safe and effective treatments; monoclonal antibodies for prophylaxis and gepants for acute therapy.
Albeit the beneficious impact of these new drugs, it is important to understand the molecular mechanisms involved to better understand migraine pathophysiology and improve the therapy. Here we describe current views on the role of the CGRP family of peptides CGRP, calcitonin (CT), adrenomedullin (AM), amylin (AMY) and their receptors in the trigeminovascular system (TGV). All these molecules are present within the TGV system but differ in expression and localization. It is likely that they have different roles, which can be utilized in providing additional drug targets.
Key words . CGRP, adrenomedullin, amylin, calcitonin, CLR, RAMPs, receptors
INTRODUCTION
Migraine is a complex disorder, known for centuries but still not fully understood. Affecting 1 billion people, migraine is one of the most prevalent, disabling neurological disorders worldwide. Migraine has a female predominance with debilitating impact in the most active years (2018; GBD 2016 Disease and Injury Incidence and Prevalence Collaborators, 2017). Currently, the migraine attack is proposed to start in the central nervous system (CNS), mainly involving regions such as hypothalamus and brainstem (Goadsby, Holland, Martins-Oliveira, Hoffmann, Schankin & Akerman, 2017). Evidence of migraine initiating in the CNS has been demonstrated in longitudinal neuroimaging studies over 30 days in spontaneous migraine attacks (Schulte, Mehnert & May, 2020; Schulte, Menz, Haaker & May, 2020). The studies revealed that hypothalamic activation during the premonitory phase of a spontaneous migraine attack, and ictally there was activity in brainstem regions often discussed in migraine. However, the link with the trigeminovascular (TGV) system and the CNS is still unclear; either the CNS is the sole activator of the trigeminal nucleus caudalis (TNC) and subsequently the TGV system or the incoming signals from the TGV system can be modified by brainstem nuclei. Following activation of the 1st order neurons in the TG, the sensory nerve fibres transmit pain signals to the lower brainstem and spinal cord C1 - C3, verified in tracing studies, and send signals to second order ascending neurons to various CNS regions such as brainstem nuclei and thalamus (Edvinsson, 2011).
Until 25 years ago, neurologists had few, and often insufficient, options to treat patients with acute migraine attacks apart from general analgesics alone or in combinations. Understanding the mechanisms of ergotamine related molecules resulted in development of the triptan group of acute medications; acting with high specificity on serotonin (5-HT1B and 5-HT1D) receptors. The triptans may act via at least 3 sites; (i) they are cranial vasoconstrictors with possibility of cardiovascular side-effects (Saxena & Den Boer, 1991), (ii) they inhibit neuropeptide release (Amrutkar, Ploug, Hay-Schmidt, Porreca, Olesen & Jansen-Olesen, 2012; Goadsby & Edvinsson, 1994), and (iii) may inhibit second-order neurons of the TGV pain pathway (Goadsby & Knight, 1997).
Due to the high probability of cardiovascular adverse events, there was a need for new drugs without vasoconstrictor effects. This work lead to a new group of prophylactic agents, monoclonal antibodies (mAbs) towards CGRP or selective binding to CGRP receptor components. These new mAbs have since proven to be effective and have few side-effects (Edvinsson, Haanes, Warfvinge & Krause, 2018). Currently, upcoming additions to acute anti-migraine pharmacotherapy includes the 5-HT1Freceptor class of agonists, the ditans (Labastida-Ramirez et al., 2020), and the CGRP receptor antagonists, the gepants (Edvinsson, Haanes, Warfvinge & Krause, 2018).
This review provides a brief description of mechanistic actions of the molecules acting through CGRP related mechanisms in relation to migraine therapy, and discusses the actions based on available molecular data. Combined, we propose ways towards improving therapy of acute and prophylactic treatments of migraine at sites involving other members of the CGRP family of peptides.