Calcitonin Gene-Related Peptide (CGRP) and Cluster Headache

Abstract

Cluster headache (CH) is a severe primary headache with a prevalence of 1/1000 individuals, and a predominance in men. Calcitonin gene-related peptide (CGRP) is a potent vasodilator, originating in trigeminal neurons and has a central role in CH pathophysiology. CGRP and the CGRP receptor complex have recently taken center stage as therapeutic targets for primary headaches, such as migraine. Multiple CGRP and CGRP receptor monoclonal antibodies, as well as small molecule antagonists (gepants) are on their way constituting a new frontier of migraine and possibly CH medication. During a CH attack, there is an activation of the trigeminal-autonomic reflex with the release of CGRP, and inversely if CGRP is administered to a CH patient in an active disease phase, it triggers an attack. Increased levels of CGRP have been found in ipsilateral jugular vein blood during the active phase of CH. This process is hypothesized to have a key role in the intense pain perception and in the associated distinctive vasodilation. So far, clinical tests of CGRP antibodies have been inconclusive in CH patients. This review summarizes the current state of knowledge on the role of CGRP in CH pathology, and as a target for future treatments.

Keywords: antibodies; genetics; neurovascular; receptor; vasodilator.

Figure 1

Calcitonin gene-related peptide (CGRP) and the CGRP receptor component receptor activity-modifying protein 1 (RAMP1) distribution using immunohistochemistry in rat brain, (modified from Warfvinge and Edvinsson, Cephalalgia 2019 [24]). Nuclei are stained blue with DAPI. In cortex (A), CGRP (left panel) is localized to neuronal cell bodies in cortical layers II-VI. Insert confirms the cytoplasmic location, and granular pattern of CGRP staining, as well as the lack of staining in neuronal processes. RAMP1 (right panel) was localized in processes and found to travel in all directions, horizontal, between layers or spanning through the entire gray matter. In the paraventricular hypothalamic nucleus (B), the distribution of CGRP and RAMP1 was similar; CGRP being localized to the cytoplasm of neurons, while RAMP1 was present in cellular processes. In the trigeminal ganglion (C), both CGRP and RAMP1 are observed in cell bodies. CGRP was localized to small and medium-sized neurons, and to thin neuronal processes. RAMP1, in contrast, was observed in larger neurons and thicker processes.

Figure 2

The CGRP receptor complex which consists of a G protein-coupled receptor called calcitonin receptor-like receptor (CALCRL), and a single transmembrane domain protein receptor, receptor activity-modifying protein (RAMP1) and two cytoplasmic proteins, receptor coupling protein (RCP) and the α-subunit of the GS protein (Gα_S).

Figure 3

Main sites of action for CGRP in cluster headache. CGRP originates in the trigeminal ganglion with sensory C- and Aδ-fibers that project to various parts of the face and head, as well as to intracranial structures.