Advances in migraine and headache therapy (BJP 75th anniversary)

This article is part of a themed issue on Advances in Migraine and Headache Therapy (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.3/issuetoc Headache disorders are globally ubiquitous, and a major source of disability. In 2019 headache was ranked 14th overall for global causes of disability adjusted life years, rose to 10th place for females, and ranked 2nd and 5th amongst individuals aged 10–24 and 25–49, respectively (Collaborators, 2020; Steiner et al., 2020). Tension type headaches are the most common headache disorder but are commonly treated with non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol/acetaminophen. Comparatively, migraine, medication overuse headache (MOH), and post-traumatic headache (PTH) are associated with far greater levels of disability (2017). Migraine alone affects ~14% of the population world-wide; and the greatest health burden associated with migraine is observed in women during their reproductive years (Ashina, Katsarava, et al., 2021; Vetvik & MacGregor, 2021). Despite its high prevalence, headache treatments are often only partially effective or are poorly tolerated (Ford et al., 2017). The recent clinical success of antibodies and small molecule inhibitors targeting calcitonin gene-related peptide (CGRP) and CGRP receptor has been a real boon for headache patients (Edvinsson et al., 2018). However, there continues to be patients that do not respond to CGRP-based therapies or experience breakthrough headache. There is clearly a need for diversification of the migraine therapeutic toolbox. This special issue on advances in migraine and headache therapy highlights major breakthroughs and emerging concepts in the field. Compared to other pain disorders or neurological conditions, the study of migraine has often been undervalued and its patients stigmatized. However, the last decade has been an exciting time for the development of successful migraine therapies, and consequently there is growing interest in the field. The approval of CGRP targeting therapies for migraine has been a huge advance in the field and resulted in major improvements in patient care and quality of life. In this special issue of the British Journal of Pharmacology, there are 4 papers discussing the role of the CGRP family of peptides and their receptors with the overall goal to examine if there might be other ways to modify activity in the trigeminovascular system in order to find new anti-migraine targets. Rees et al. ask if there are targets beyond CGRP. This is followed up by Garelja et al. who propose that an antagonist at the amylin AMY1 receptor might be such a mechanism. Garelja et al. provides a second paper on the detailed characterization of calcitonin and calcitonin receptor-like receptor illustrating differences between mouse and human receptors, an aspect that is important to consider in the discovery of novel therapies. Edvinsson et al. illustrate the expression of the CGRP family of peptides and their receptors in the trigeminovascular system of rat and man. In support of Garelja et al., there are differences between rat and man; however, one caveat is that the material from experimental animals can be harvested optimally while the tissue from man often relies on autopsy material and hence might to some degree be compromised. Figure 1 shows the overall expression of the receptors. In both rat and man, there is a rich supply of CGRP receptors in satellite glial cells and in the large neurons in the trigeminal ganglion, the latter forming the Aδ-fibres. Amylin 1 receptors were seen in the large neurons to co-localize with the CGRP receptor in both rat and man. Thus, the morphology would agree with the molecular biology of Garelja et al. The expression of the CGRP family of peptides in the trigeminal ganglion is shown in Figure 1. Overall, there is a very rich expression of CGRP, both protein and mRNA in the small to mid-sized neurons that form the C-fibres in peripheral direction to various parts of the cranial tissues and to the brainstem, primarily the trigeminal nucleus caudalis. In the paper by Edvinsson et al., the work points towards some contribution and co-storage with amylin in neurons while adrenomedullin primarily localize in the vascular endothelium. From the morphological point of view, it is argued that the role of amylin would differ from that of CGRP. A major source of amylin is from the pancreas. Thus in the circulation its levels are 10 times higher than that of CGRP. Noting that the trigeminal ganglion is outside of the blood–brain barrier amylin may engage with the trigeminovascular system from the blood at this point. Garelja illustrates that CGRP might act on both the CGRP receptor and the AMY1 receptor; however, there is a difference in affinity of nearly 100 times. Gepants and the monoclonal antibody erenumab are highly specialized for the CGRP receptor; hence, their effects are primarily directed at the CGRP receptor but could have some effect also on the AMY1 receptor. The future role of the CGRP family of peptides in pain and in headache disorders is still in play, and the complexity is very well illustrated by Rees et al. Another neuropeptide, the pituitary adenylate cyclase activating polypeptide (PACAP), has also been implicated in migraine. PACAP is part of the glucagon-growth hormone releasing factor-secretin superfamily which includes vasoactive intestinal polypeptide (VIP) (Vaudry et al., 2000). PACAP-38 is the predominant form expressed in the brain, and PACAP-38 levels are upregulated during migraine attacks (Tuka et al., 2013), and decrease following successful pharmacological intervention (Zagami et al., 2014). Furthermore, infusion of PACAP-38 evokes migraine-like headache in migraine patients, and to a lesser extent in healthy controls (Schytz et al., 2009). PACAP binds to the G protein coupled receptors: VPAC1, VPAC2, and with high affinity to the PAC1 receptor. Drug development has focused on developing antibodies targeting PACAP or the PAC1 receptor. However, a recent Phase 2 clinical trial of an anti-PAC1 receptor antibody showed no clinical benefit over placebo in migraine patients (Ashina, Doležil, et al., 2021). In this special issue, Tasma et al. (Tasma, 2022) explore the pharmacology of potential PAC1 splice variants. They show that the most commonly studied the PAC1n variant, shows distinct pharmacological properties to the N-terminally deleted variant, PAC1s. Intriguingly, they show that the efficacy of PACAP receptor antagonists varies depending on the PACAP/VIP peptides present. These findings have important implications for drug discovery. This study demonstrates the importance of proper pharmacological characterization, and illustrates how little is known about the signalling properties of the PACAPergic system. The serotonergic system has long been implicated in migraine. The triptans, 5-HT1B/1D agonists, were the first specific therapy ever approved for migraine in the 1990s. To this day, triptans are still the first line treatment of acute attacks for migraine patients. However, there are 15 types of 5-HT receptors that are broadly expressed throughout the body and brain. Giniatullin reviews the role of 5-HT receptors in migraine, with a special emphasis on the ionotropic 5-HT3 receptor (Giniatullin, 2022). The 5-HT1F receptor agonist, lasmiditan, has emerged as a novel approved therapy for migraine patients. This drug class, known as ditans, represent the first migraine therapy devoid of effects on the vasculature; and therefore open therapeutic options for migraine patients with co-morbid cardiovascular diseases. In this issue, Vila-Pueyo and colleagues provide insight on the mechanism of action of ditans. In human post-mortem tissue they find that 5-HT1F receptor mRNA is found in cells within the trigeminal ganglia and cortex, but not within the cortex microvasculature (Vila-Pueyo, 2021). These results support the idea that ditans have their effect at sites within the central as well as the peripheral nervous system. Intriguingly, this study also found that 5-HT1F receptor activation was effective in a physiological model of cluster headache (Vila-Pueyo, 2021), a patient group with limited treatment options. It is an exciting time to be studying headache disorders. The approval of novel therapies targeting CGRP and 5-HT1F illustrates the power of thoughtful and tenacious scientists. In the migraine field, basic, translational, and clinical research is highly integrated, thus better informing drug development. As illustrated in this special issue there are many new targets on the horizon, and we hope to continue to expand the treatment toolbox.