Cortical spreading depression as a site of origin for migraine: Role of CGRP

Abstract

Premise: Migraine is a complex neurologic disorder that leads to significant disability, yet remains poorly understood.

Problem: One potential triggering mechanism in migraine with aura is cortical spreading depression, which can activate the trigeminal nociceptive system both peripherally and centrally in animal models. A primary neuropeptide of the trigeminal system is calcitonin gene-related peptide, which is a potent vasodilatory peptide and is currently a major therapeutic target for migraine treatment. Despite the importance of both cortical spreading depression and calcitonin gene-related peptide in migraine, the relationship between these two players has been relatively unexplored. However, recent data suggest several potential vascular and neural connections between calcitonin gene-related peptide and cortical spreading depression.

Conclusion: This review will outline calcitonin gene-related peptide-cortical spreading depression connections and propose a model in which cortical spreading depression and calcitonin gene-related peptide act at the intersection of the vasculature and cortical neurons, and thus contribute to migraine pathophysiology.

Keywords: Neurovasculature; cortical spreading depression; trigeminal nerve; vasodilation.

Figure 1.

Model of CGRP at the intersection of vascular-neural communication. The steps involved in this bidirectional communication are organized from 1 to 4. Step 1: CSD activates meningeal afferents of the trigeminal nerve and multiple CSD events can increase central CGRP mRNA and peptide release in the cerebral cortex. Step 2: Peripheral CGRP released from trigeminal afferents causes vasodilation and alters the trigeminovascular microenvironment, resulting in more CGRP release. This positive feedback loop would prolong the local vasodilation of meningeal vessels, including pial arterioles, which leads to reflex autoregulation of cerebral blood flow (CBF). This further dilates arterioles in the pia and brain parenchyma. Step 3: Increased flow in parenchymal vessels transmits a signal resulting in increased neuronal firing rates by vascular-neural coupling, as observed in cortical slices. Step 4: Release of central CGRP from cortical neurons acts as a neuromodulator to increase synaptic signaling and causes further vasodilation of parenchymal arterioles. The vasodilation would potentially create a self-sustaining positive feedback loop through vascular-neural activation to maintain increased neural activity and CGRP release. CGRP is represented by the green circles.