Calcitonin gene-related peptide (CGRP): role in migraine pathophysiology and therapeutic targeting

Abstract

Introduction: The neuropeptide calcitonin gene-related peptide (CGRP) is recognized as a critical player in migraine pathophysiology. Excitement has grown regarding CGRP because of the development and clinical testing of drugs targeting CGRP or its receptor. While these drugs alleviate migraine symptoms in half of the patients, the remaining unresponsive half of this population creates an impetus to address unanswered questions that exist in this field.Areas covered: We describe the role of CGRP in migraine pathophysiology and CGRP-targeted therapeutics currently under development and in use. We also discuss how a second CGRP receptor may provide a new therapeutic target.Expert opinion: CGRP-targeting drugs have shown a remarkable safety profile. We speculate that this may reflect the redundancy of peptides within the CGRP family and a second CGRP receptor that may compensate for reduced CGRP activity. Furthermore, we propose that an inherent safety feature of peptide-blocking antibodies is attributed to the fundamental nature of peptide release, which occurs as a large bolus in short bursts of volume transmission. These facts support the development of more refined CGRP therapeutic drugs, as well as drugs that target other neuropeptides. We believe that the future of migraine research is bright with exciting advances on the horizon.

Keywords: CGRP; Migraine; gepants; monoclonal antibodies; trigeminovascular system.

Figure 1.

CGRP and CGRP receptor distribution in the peripheral and central nervous systems. A) In the brain, CGRP and its receptors are present in the thalamus, the amygdala, periaqueductal grey, locus coeruleus, trigeminal nucleus caudalis, parabrachial nucleus, hypothalamus, and the cerebellum. The receptors can also be found at the meningeal vasculature. B) CGRP is released from trigeminal axons onto blood vessels in the meninges where it is involved in vasodilation and activation of trigeminal neurons. CGRP targeting drugs likely act at this site to treat migraine. C) CGRP is released in the trigeminal ganglion by small C fibers and binds to its receptors on other neurons (Aδ fibers) and glial cells triggering neurogenic inflammation. CGRP targeting drugs likely act at this site to treat migraine since the trigeminal ganglion is located outside of the BBB. While the AMY₁ receptor can also be found in the trigeminal ganglion, the CGRP receptor and the AMY₁ receptor do not seem to colocalize on the same neuron at this site [87]. CGRP and the CGRP receptor are rarely co-localized on the same neuron. At this point, it is still unknown if AMY₁ can be expressed on CGRP containing cells and our schematic representing both on the C fiber is still speculation. It is also unknown if the glial cells only express the CGRP receptor or also express AMY₁. The schematic art used in this figure were provided by Servier Medical art (http://servier.com/Powerpoint-image-bank).