The big CGRP flood - sources, sinks and signalling sites in the trigeminovascular system

Karl Messlinger

doi:10.1186/s10194-018-0848-0

Abstract

BackgroundCalcitonin gene-related peptide (CGRP) has long been a focus of migraine research, since it turned out that inhibition of CGRP or CGRP receptors by antagonists or monoclonal IgG antibodies was therapeutic in frequent and chronic migraine. This contribution deals with the questions, from which sites CGRP is released, where it is drained and where it acts to cause its headache proliferating effects in the trigeminovascular system.ResultsThe available literature suggests that the bulk of CGRP is released from trigeminal afferents both in meningeal tissues and at the first synapse in the spinal trigeminal nucleus. CGRP may be drained off into three different compartments, the venous blood plasma, the cerebrospinal fluid and possibly the glymphatic system. CGRP receptors in peripheral tissues are located on arterial vessel walls, mononuclear immune cells and possibly Schwann cells; within the trigeminal ganglion they are located on neurons and glial cells; in the spinal trigeminal nucleus they can be found on central terminals of trigeminal afferents. All these structures are potential signalling sites for CGRP, where CGRP mediates arterial vasodilatation but not direct activation of trigeminal afferents. In the spinal trigeminal nucleus a facilitating effect on synaptic transmission seems likely. In the trigeminal ganglion CGRP is thought to initiate long-term changes including cross-signalling between neurons and glial cells based on gene expression. In this way, CGRP may upregulate the production of receptor proteins and pro-nociceptive molecules.ConclusionsCGRP and other big molecules cannot easily pass the blood-brain barrier. These molecules may act in the trigeminal ganglion to influence the production of pronociceptive substances and receptors, which are transported along the central terminals into the spinal trigeminal nucleus. In this way peripherally acting therapeutics can have a central antinociceptive effect.

Highlights

Calcitonin gene-related peptide (CGRP) has long been a focus of migraine research, since it turned out that inhibition of CGRP or CGRP receptors by antagonists or monoclonal IgG antibodies was therapeutic in frequent and chronic migraine
An increase in jugular plasma CGRP was measured following topical application of depolarizing concentrations of potassium chloride (KCl) onto the exposed rat parietal dura mater [8] suggesting that CGRP released from dural afferent fibres is taken up into the meningeal venous system and transported via the sagittal sinus to the jugular vein (Fig. 1a)
Since blood vessels supplying the ganglion do not have a blood-brain barrier (BBB), like those supplying the cranial dura [18], the released CGRP is drained via the venous plasma and can contribute to the plasma CGRP values measured in jugular blood (Fig. 1b)

Summary

Introduction

Calcitonin gene-related peptide (CGRP) has long been a focus of migraine research, since it turned out that inhibition of CGRP or CGRP receptors by antagonists or monoclonal IgG antibodies was therapeutic in frequent and chronic migraine. The cranial dura mater is innervated by CGRP immunoreactive nerve fibres running along the meningeal arteries and terminating at their branches and between blood vessels in the connective tissue [38].

Results

Conclusion