The Role of Meningeal Immune Cells in the Efficacy of CGRP-based Migraine Therapies

Abstract

Migraine is a painful, chronic neurological disorder that represents the second most disabling illness worldwide. There are two prominent mechanisms thought to contribute to migraine pain: immune cell activation and calcitonin gene-related peptide (CGRP) signaling. Cortical spreading depression (CSD), thought to underlie the aura that precedes migraine attack in a subpopulation of migraineurs, is associated with increased meningeal macrophage activation. Macrophages can activate meningeal primary afferent neurons and contribute to migraine pain through release of pro-inflammatory cytokines. CSD also increases CGRP synthesis and release, and single-cell RNA sequencing data support the expression of CGRP receptor subunit mRNA in mouse meningeal immune cells. The efficacy of CGRP receptor antagonists as migraine therapies support the critical role of CGRP in the development of migraine pain. However, the mechanism of action of these drugs is incompletely understood. Given the effect of CSD on immune cell activation and CGRP release, the presence of CGRP receptor on immune cells, and the use of CGRP receptor antagonists to treat migraine, the following study uses anatomical, functional, and behavioral approaches to assess the role of meningeal immune cells in the efficacy of CGRP-based migraine therapies. This is done in the context of a minimally invasive model of migraine with aura (optogenetic spreading depression, OSD). I plan to characterize OSD-dependent changes in CGRP receptor expression in meningeal immune cells, assess the ability of CGRP receptor antagonists to prevent OSD-induced changes in macrophage activation, and determine the contribution of macrophage CGRP receptors to OSD-induced pain. The outcomes of these experiments may not only reveal a mechanism underlying the therapeutic efficacy of CGRP antagonists but potentially novel targets and mechanisms to improve existing migraine therapies. Grant support from R01 NS122784.