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.
Highlights
Anatomical Basis of Headache Generation. Primary headaches such as tension-type headache, migraine or trigemino-autonomic headaches are clinically well characterized, despite intense basic and clinical research, their origin remains still largely in the dark. In this contribution we ask whether sensitization of nociceptors may contribute to the generation of primary headaches [1] and how transduction channels of the transient receptor potential (TRP) type, which are typically expressed in nociceptors [2], are involved in the expected sensitizing mechanisms
The trigeminal nociceptors consist of small primary sensory neurons with unmyelinated Cand thinly myelinated Aδ-fibers, the central terminals of which run through the trigeminal nerve, enter the pontine brainstem and synapse on neurons in the spinal trigeminal nucleus (STN)
Using DiI tracing, dental primary afferents have been shown responding to hyperosmotic stimuli with calcium transients, which were dependent on transient receptor potential melastatin 8 (TRPM8) activation [42]
Summary
Primary headaches such as tension-type headache, migraine or trigemino-autonomic headaches are clinically well characterized, despite intense basic and clinical research, their origin remains still largely in the dark. In this contribution we ask whether sensitization of nociceptors may contribute to the generation of primary headaches [1] and how transduction channels of the transient receptor potential (TRP) type, which are typically expressed in nociceptors [2], are involved in the expected sensitizing mechanisms. The trigeminal nociceptors consist of small primary sensory neurons with unmyelinated Cand thinly myelinated Aδ-fibers, the central terminals of which run through the trigeminal nerve, enter the pontine brainstem and synapse on neurons in the spinal trigeminal nucleus (STN). The meninges are densely innervated by postganglionic sympathetic fibers and sparsely by parasympathetic fibers originating in the cranial ganglia [4]
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