C-fibers may modulate adjacent Aδ-fibers through axon-axon CGRP signaling at nodes of Ranvier in the trigeminal system

Edvinsson, Jacob C A; Warfvinge, Karin; Krause, Diana N.; Blixt, Frank W; Sheykhzade, Majid; Edvinsson, Lars; Haanes, Kristian Agmund

doi:10.1186/s10194-019-1055-3

Cited by 82 publications

(96 citation statements)

References 50 publications

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“…They may be activated by CGRP released from central terminals of other trigeminal afferents to facilitate neurotransmitter release and synaptic transmission (Takhshid et al 2007). Similarly, a recent immunohistochemical study identified CGRP receptor subunits at nodes of Ranvier of Aδ fibers adjacent to CGRP-containing C fibers in the ganglia and dura (Edvinsson et al 2019). Thus, there is a possibility of cross-talk between adjacent fibers as well in cell bodies in the ganglia.…”

Section: Significance Of Intraganglionic Cross-talk For Nociceptive Tmentioning

confidence: 96%

Cross-talk signaling in the trigeminal ganglion: role of neuropeptides and other mediators

2020

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The trigeminal ganglion with its three trigeminal nerve tracts consists mainly of clusters of sensory neurons with their peripheral and central processes. Most neurons are surrounded by satellite glial cells and the axons are wrapped by myelinating and non-myelinating Schwann cells. Trigeminal neurons express various neuropeptides, most notably, calcitonin generelated peptide (CGRP), substance P, and pituitary adenylate cyclase-activating polypeptide (PACAP). Two types of CGRP receptors are expressed in neurons and satellite glia. A variety of other signal molecules like ATP, nitric oxide, cytokines, and neurotrophic factors are released from trigeminal ganglion neurons and signal to neighboring neurons or satellite glial cells, which can signal back to neurons with same or other mediators. This potential cross-talk of signals involves intracellular mechanisms, including gene expression, that can modulate mediators of sensory information, such as neuropeptides, receptors, and neurotrophic factors. From the ganglia cell bodies, which are outside the blood-brain barrier, the mediators are further distributed to peripheral sites and/or to the spinal trigeminal nucleus in the brainstem, where they can affect neural transmission. A major question is how the sensory neurons in the trigeminal ganglion differ from those in the dorsal root ganglion. Despite their functional overlap, there are distinct differences in their ontogeny, gene expression, signaling pathways, and responses to anti-migraine drugs. Consequently, drugs that modulate cross-talk in the trigeminal ganglion can modulate both peripheral and central sensitization, which may potentially be distinct from sensitization mediated in the dorsal root ganglion.

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Section: Significance Of Intraganglionic Cross-talk For Nociceptive Tmentioning

confidence: 96%

Cross-talk signaling in the trigeminal ganglion: role of neuropeptides and other mediators

2020

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“…Presynaptic terminals in nerves that produce CGRP, take the form of focal swellings, occurring at regular intervals along the axon [23]. This mechanism may occur at the molecular level via axon-axon modulation of the two types of sensory fibers [78]. The C-fibers may modulate adjacent Aδ-fibers through axon-axon CGRP signaling at nodes of Ranvier in the trigeminal system.…”

Section: Cgrp Functionmentioning

confidence: 99%

Calcitonin Gene-Related Peptide (CGRP) and Cluster Headache

2020

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Cluster headache (CH) is a severe primary headache with a prevalence of 1/1000 individuals, and a predominance in men. Calcitonin gene-related peptide (CGRP) is a potent vasodilator, originating in trigeminal neurons and has a central role in CH pathophysiology. CGRP and the CGRP receptor complex have recently taken center stage as therapeutic targets for primary headaches, such as migraine. Multiple CGRP and CGRP receptor monoclonal antibodies, as well as small molecule antagonists (gepants) are on their way constituting a new frontier of migraine and possibly CH medication. During a CH attack, there is an activation of the trigeminal-autonomic reflex with the release of CGRP, and inversely if CGRP is administered to a CH patient in an active disease phase, it triggers an attack. Increased levels of CGRP have been found in ipsilateral jugular vein blood during the active phase of CH. This process is hypothesized to have a key role in the intense pain perception and in the associated distinctive vasodilation. So far, clinical tests of CGRP antibodies have been inconclusive in CH patients. This review summarizes the current state of knowledge on the role of CGRP in CH pathology, and as a target for future treatments.

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“…As all these molecules are produced in the cell body, every mechanism interacting with their gene expression has consequences for the peripheral and central functions of these neurons. For example, CGRP receptors integrated into the presynaptic membrane of central trigeminal terminals may be activated by CGRP released from adjacent terminals of other trigeminal afferents to facilitate neurotransmitter release and synaptic transmission [67,68]. Another example is BDNF, the expression of which is enhanced by CGRP in cultured trigeminal neurons [69].…”

Section: Functional Significance Of Mediator Trafficking To Afferentmentioning

confidence: 99%

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

Dux

Rosta

Meßlinger

2020

IJMS

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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.

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C-fibers may modulate adjacent Aδ-fibers through axon-axon CGRP signaling at nodes of Ranvier in the trigeminal system

Cited by 82 publications

References 50 publications

Cross-talk signaling in the trigeminal ganglion: role of neuropeptides and other mediators

Cross-talk signaling in the trigeminal ganglion: role of neuropeptides and other mediators

Calcitonin Gene-Related Peptide (CGRP) and Cluster Headache

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

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