TRP Channels in the Focus of Trigeminal Nociceptor Sensitization Contributing to Primary Headaches

Abstract

Pain in trigeminal areas is driven by nociceptive trigeminal afferents. Transduction molecules, among them the nonspecific cation channels transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1), which are activated by endogenous and exogenous ligands, are expressed by a significant population of trigeminal nociceptors innervating meningeal tissues. Many of these nociceptors also contain vasoactive neuropeptides such as calcitonin gene-related peptide (CGRP) and substance P. Release of neuropeptides and other functional properties are frequently examined using the cell bodies of trigeminal neurons as models of their sensory endings. Pathophysiological conditions cause phosphorylation, increased expression and trafficking of transient receptor potential (TRP) channels, neuropeptides and other mediators, which accelerate activation of nociceptive pathways. Since nociceptor activation may be a significant pathophysiological mechanism involved in both peripheral and central sensitization of the trigeminal nociceptive pathway, its contribution to the pathophysiology of primary headaches is more than likely. Metabolic disorders and medication-induced painful states are frequently associated with TRP receptor activation and may increase the risk for primary headaches.

Hemokinin-1 Gene Expression Is Upregulated in Trigeminal Ganglia in an Inflammatory Orofacial Pain Model: Potential Role in Peripheral Sensitization

“…Satellite glial cells (SGC) and resident macrophages in the TG, as well as astrocytes and microglia in the central nervous system, are also activated in the process and contribute to the sensitization. There is growing evidence that the cross-talk between neurons and glial cells has a prominent modulatory role on nociceptive transmission under physiological and pathophysiological conditions [1][2][3][4][5][6].…”

A TRiP Through the Roles of Transient Receptor Potential Cation Channels in Type 2 Upper Airway Inflammation

“…This may take place due to their sensory roles in the context of infection (e.g., by sensing LPS [95][96][97]) or through the detection of exogenous noxious chemicals or endogenous molecules signaling tissue damage [21,98]. Most interest has been put in TRPV1 and TRPA1, which often colocalize with neuropeptides such as substance P (SP), calcitonin gene-related peptide (CGRP), and neurokinin A (NKA) [99][100][101]. NHR is suspected to be caused by overactivity or sensitization of these TRP channels on sensory afferent neurons, leading to release of neuropeptides in the mucosal and submucosal space, triggering vasodilation and mucus secretion [15••].…”

Petasin and isopetasin reduce CGRP release from trigeminal afferents indicating an inhibitory effect on TRPA1 and TRPV1 receptor channels

“…TRPV1 receptor channels are expressed by the majority of nociceptive trigeminal afferents, mostly C-fiber but also a minority of Aδ fiber afferents. Interestingly, 70% of CGRP-immunoreactive neurons were found to be colocalized with TRPV1 channels [ 10 , 11 ].…”