Dural Immune Cells, CGRP, and Migraine

Abstract

Migraine is the most common neurological disorder in the world, affecting 12% of the population. Migraine involves the central nervous system, trigeminal nerves and meninges. Recent advances have shown that targeting calcitonin gene-related peptide (CGRP) through either antibodies or small molecule receptor antagonists is effective at reducing episodic and chronic migraine episodes, but these therapeutics are not effective in all patients. This suggests that migraine does not have a singular molecular cause but is likely due to dysregulated physiology of multiple mechanisms. An often-overlooked part of migraine is the potential involvement of the immune system. Clinical studies have shown that migraine patients may have dysregulation in their immune system, with abnormal plasma cytokine levels either during the attack or at baseline. In addition, those who are immunocompromised appear to be at a higher risk of migraine-like disorders. A recent study showed that migraine caused changes to transcription of immune genes in the blood, even following treatment with sumatriptan. The dura mater is densely packed with macrophages, mast and dendritic cells, and they have been found to associate with meningeal blood vessels and trigeminal afferent endings. Recent work in mice shows activation and morphological changes of these cells in rodents following the migraine trigger cortical spreading depression. Importantly, each of these immune cell types can respond directly to CGRP. Since immune cells make up a large portion of the dura, have functional responses to CGRP, and interact with trigeminal afferents, CGRP actions on the dural immune system are likely to play key roles in migraine.

The Special One: Architecture, Physiology and Pharmacology of the TRESK Channel

“…TRESK activation / overexpression does not only modulate the firing rate but also inhibits the release of substance P and the vasodilative peptide CGRP [61,[63][64][65]. Both peptides act as important neurotransmitters and are involved in pain transmission and in (neuro)inflammation [66,67]. Thus, TRESK function might play an important role in distinct inflammatory processes as well, which is strengthened by many different studies [33,[68][69][70][71].…”

OnabotulinumtoxinA: Still the Present for Chronic Migraine

“…Furthermore, the action of CGRP on pericytes at the endothelial levels determines an increase in the permeability of meningeal arteries [ 27 ]. Furthermore, the degranulation of meningeal mast cells has been linked to trigeminal nerve fiber activation [ 28 ]. It should be noticed that meningeal immune cells and CGRP are a growing field of research, but their relationship has not been completely unveiled yet.…”

“…It should be noticed that meningeal immune cells and CGRP are a growing field of research, but their relationship has not been completely unveiled yet. Despite this, readers may find an exhaustive review on this topic [ 28 ]. Moreover, CGRP also binds upon its receptors located on the Aδ-fibers, thus activating the PKA pathway and, consequently, trigeminal fiber sensitization [ 29 ].…”

Role of ATP in migraine mechanisms: focus on P2X3 receptors

“…Meningeal tissues contain various immune cells [ 77 , 78 ]. Of special interest are local mast cells which synthesize a plethora of active molecules including ATP, hormones, cytokines, neurotrophins, all to be released in a stimulus-specific manner [ 79 , 80 ].…”

“…While the neuropeptide CGRP is considered a major contributor to the onset of migraine attacks [ 12 ] and has multifarious effects on neurons and immune cells in the CNS [ 78 ], we propose that one important target for the CGRP algogenic action is the P2X3 receptor. Progress in understanding the molecular mechanisms of such an action of CGRP has come from the use of an in vitro model of mouse trigeminal ganglia where it has been shown that CGRP (at submicromolar concentrations) selectively binds to sensory neurons expressing P2X3 receptors without generating any direct change in their membrane current [ 16 , 93 ].…”