Neuropeptides and the Nodes of Ranvier in Cranial Headaches

Abstract

The trigeminovascular system (TGV) comprise of the trigeminal ganglion with neurons and satellite glial cells, with sensory unmyelinated C-fibers and myelinated Aδ-fibers picking up information from different parts of the head and sending signals to the brainstem and the central nervous system. In this review we discuss aspects of signaling at the distal parts of the sensory fibers, the extrasynaptic signaling between C-fibers and Aδ-fibers, and the contact between the trigeminal fibers at the nerve root entry zone where they transit into the CNS. We also address the possible role of the neuropeptides calcitonin gene-related peptide (CGRP), the neurokinin family and pituitary adenylyl cyclase-activating polypeptide 38 (PACAP-38), all found in the TGV system together with their respective receptors. Elucidation of the expression and localization of neuropeptides and their receptors in the TGV system may provide novel ways to understand their roles in migraine pathophysiology and suggest novel ways for treatment of migraine patients.

Keywords: Redlich-Obersteiner zone; Remak bundles; nerve entry zone; nodes of Ranvier; trigeminal ganglion; vascular neuroeffector site.

FIGURE 1

Confocal visualization of the node of Ranvier. Confocal microscopy displaying calcitonin gene-related peptide (CGRP) (red) immunreactive C-fiber boutons flanked by two Aδ-fibers with their paranodal regions marked with contactin associated protein 1 (CASPR, green). This close relationship between the two fiber types display a point of interaction for CGRP signaling within the trigeminovascular (TGV) system (see Supplementary Video). For experimental details on antibodies etc., see Edvinsson et al. (2019).

FIGURE 2

Schematic illustration of the differential distribution of the CGRP, pituitary adenylyl cyclase-activating polypeptide (PACAP), and Neurokinin signaling compounds in the trigeminal system. The illustration suggests possible site of origin if the various peptides and their associated release. Further, the receptor expression highlights possible receptor targets, following the peptide release. The expression is based on immunology findings from the following studies (Edvinsson et al., 2019, 2021; Edvinsson J. C. A. et al., 2020; Edvinsson L. et al., 2020).