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

Abstract

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.

Resolvin D3 controls mouse and human TRPV1-positive neurons and preclinical progression of psoriasis

“…Apart from its well-known roles in vasodilation and neuroimmune signaling, CGRP signaling and its inhibition have recently emerged as novel therapeutic approaches for migraine with several US Food and Drug Administration (FDA)-approved drugs currently on the market 79 . Although several data suggest a critical role for CGRP in psoriasis 50 , 76 , 77 , 80 , the therapeutic potential of its inhibition has only been investigated recently and remains controversial, showing minimal or no effects in psoriasiform skin inflammation and itch using global CGRP knockout mice or after the administration of CGRP receptor antagonist BIBN4096 49 .…”

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

“…Other neuropeptides released from peptidergic sensory neurons have already been suggested to have a prominent role in glial cell activation during sensitization. Among these, CGRP, which has a clinically proven role in migraine headaches [99], appears to be a key mediator of the neuron-glia interactions in the TG [4,100,101]. HK-1 could be a neuropeptide participating in two-way communication between sensory neurons and satellite glial cells.…”

“…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].…”

Protective Effects of Hydrogen Sulfide Against the ATP-Induced Meningeal Nociception

“…The novel members of expanding family of gaseous transmitters represent a group of such molecules which may exhibit either pro- or anti-nociceptive effects in migraine. One well-established migraine promoting gas is NO which has multiple vascular and neuronal targets in the trigeminovascular system (Messlinger et al, 2000 , 2020 ; Marone et al, 2018 ). Another gaseous transmitter, carbon monoxide (CO) also recently emerged as a novel trigger of migraine (Arngrim et al, 2014 ).…”

“…Long-lasting migraine pain likely originating from meninges, involves local inflammation, sensitization and activation of trigeminal afferents by multiple endogenous compounds released from local vessels, somatic and parasympathetic nerves and various immune cells such as mast cells occupying this area (Bolay et al, 2002 ; Levy et al, 2007 ; Olesen et al, 2009 ; Burstein et al, 2015 ; Koroleva et al, 2019 ). To find new pharmacological interventions in migraine, much attention is currently paid to the substances triggering pain such as neuropeptides, most notably, calcitonin gene-related peptide (CGRP) which promote neurogenic inflammation in meninges (Ebersberger et al, 1999 ; Lassen et al, 2002 ; Schou et al, 2017 ) or gaseous transmitter nitric oxide (NO) promoting pain and dilating cortical vessels (Reuter et al, 2001 ; Pryazhnikov et al, 2014 ; Messlinger et al, 2020 ). Less interest is given to endogenous molecules which can exhibit the anti-nociceptive and anti-inflammatory effects in migraine.…”