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Review
. 2022 Nov 9:16:929136.
doi: 10.3389/fnins.2022.929136. eCollection 2022.

Peripheral role of glutamate in orofacial pain

Jinyue Liu  1   2 , Shilin Jia  1   2 , Fang Huang  2 , Hongwen He  2 , Wenguo Fan  1   2
Affiliations
Review

Peripheral role of glutamate in orofacial pain

Jinyue Liu et al. Front Neurosci. .

Abstract

Glutamate is the principal excitatory neurotransmitter in the central nervous system. In the periphery, glutamate acts as a transmitter and involves in the signaling and processing of sensory input. Glutamate acts at several types of receptors and also interacts with other transmitters/mediators under various physiological and pathophysiological conditions including chronic pain. The increasing amount of evidence suggests that glutamate may play a role through multiple mechanisms in orofacial pain processing. In this study, we reviewed the current understanding of how peripheral glutamate mediates orofacial pain, how glutamate is regulated in the periphery, and how these findings are translated into therapies for pain conditions.

Keywords: glutamate; glutamate receptors; glutamate transporters; orofacial pain; trigeminal ganglion.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Molecular families of glutamate receptors. The two main glutamate receptors are each composed of three functional definition groups of the receptor. Numerous individual subunits, encoded by different genes, make up these receptors. iGluRs, ionotropic glutamate receptors; mGluRs, metabotropic glutamate receptors; NMDA, N-methyl-D-aspartic acid; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid.
FIGURE 2
FIGURE 2
Glutamine cycle in the trigeminal nervous system. Glu can be taken up by neurons or glia. In neurons, glutamate is taken up by EAAT. Satellite glial cells take up glutamate via EAAT for conversion to Gln via GS. Glutamine can be transported back to neurons for conversion to Glu by GLS, and then Glu can be packaged into vesicles by VGLUT. In addition to the glutamine cycle, neuron and glial cells also produce glutamate via interactions with the neuronal TCA cycle. Glu, glutamate; EAAT, excitatory amino acid transporter; Gln, glutamine; GS, glutamine synthetase; GLS, glutaminase; VGLUT, vesicular glutamate transporters; TCA, tricarboxylic acid.
FIGURE 3
FIGURE 3
Peripheral glutamate mechanisms. Peripheral glutamate plays an important role in the transmission of nociception under normal and pathological conditions. Macrophages, mast cells, and dendritic cells in the epidermis and dermis are important endogenous sources of glutamate, which can be transported by EAAT. Glutamate binds to receptors and activates PLC, leading to intracellular Ca2+ release and PKCε activation, which ultimately activates TRP ion channels to mediate peripheral sensation. TG neurons store glutamate in vesicles (black circles) for release in the peripheral and central nervous. With the presence of noxious stimulation, nerve endings release glutamate stored in vesicles into peripheral tissues. Glutamate released from the same or a nearby terminal can interact with Glu R to activate or sensitize the terminals. CNS, central nervous system; PLC, phospholipase C; PKCε, protein kinase C epsilon; Glu R, glutamate receptor; TRP, transient receptor potential; SGC, satellite glial cell.
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