Meningeal neuropeptide and neuroimmune interactions in the context of migraine

Migraine is a highly prevalent, painful neurological disorder with increasing evidence to support the contribution of neuroimmune interactions to its pathophysiology. The cranial meninges are a key site of these interactions, and are characterized by rich innervation, vascular and lymphatic supply, connective tissue, and diverse immune cell populations. Migraine-related physiological events, such as cortical spreading depression and other external triggers, induce the release of neuropeptides, including calcitonin gene-related peptide (CGRP), substance P (SP), pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP), and neuropeptide Y (NPY). These neuropeptides subsequently act on immune cell subtypes to promote cytokine release, thereby driving the bidirectional relationship between meningeal immune cells and neuronal innervation. Recent therapies targeting neuropeptide signaling, particularly CGRP, have validated the importance of these systems. However, gaps remain in the understanding of how neuropeptide signaling shapes meningeal immune responses in the context of the time course of a migraine attack, where the headache phase may be preceded by a triggering event, a prodrome, and an aura, and followed by a postdrome. This review summarizes the existing literature on the effects of neuropeptide signaling on immune cells as it relates to migraine pathophysiology and highlights the gaps in knowledge that need to be addressed to better understand migraine mechanisms and inform future therapeutic strategies.