The nervous system is built from two broad categories of cells: neurons and glial cells. The main glial cell types are, in the central nervous system, astrocytes and oligodendrocytes and, in the peripheral nervous system, Schwann cells, enteric glial cells and satellite cells. (Jensen, 2004)
Radial glia, astrocytes, oligodendrocyte progenitor cells, oligodendrocytes, and microglia each influence nervous system development, from neuronal birth, migration, axon specification, and growth through circuit assembly and synaptogenesis. As neural circuits mature, distinct glia fulfill key roles in synaptic communication, plasticity, homeostasis, and network-level activity through dynamic monitoring and alteration of CNS structure and function. (Allen and Lyons, 2018).
Alterations on glia has been related with diseases such as Alzheimer's disease (Dzamba et al, 2016), alterations in the gastrointestinal immune homeostasis (Sequella et al, 2021), and various neurological disorders. (Kim et al, 2020)
Accumulating evidence suggests that non-neuronal cells such as immune cells, glial cells, keratinocytes, cancer cells, and stem cells play active roles in the pathogenesis and resolution of pain. (Ji et al, 2016) Painful syndromes are associated with different glial activation states: (1) glial reaction (ie, upregulation of glial markers such as IBA1 and glial fibrillary acidic protein (GFAP) and/or morphological changes, including hypertrophy, proliferation, and modifications of glial networks); (2) phosphorylation of mitogen-activated protein kinase signaling pathways; (3) upregulation of adenosine triphosphate and chemokine receptors and hemichannels and downregulation of glutamate transporters; and (4) synthesis and release of glial mediators (eg, cytokines, chemokines, growth factors, and proteases) to the extracellular space. (Ji et al, 2013)
Secreted CGRP in the trigeminal ganglion interacts with adjacent neurons and satellite glial cells to perpetuate peripheral sensitization and can drive central sensitization of the second-order neurons. (Iyengar et al. 2019)
Research in the field has focused on glial activation patterns using immunostaining of glial activation markers and examining glial cell hypertrophy or proliferation following inflammation or tissue injury. The molecular mechanisms of glia activation and the time course of glial activation have not been explicitly studied in orofacial pain conditions. Elucidating such mechanisms might help hijack glial activation programs for better pain control. (Ye et al, 2021)
Jessen KR. Glial cells. Int J Biochem Cell Biol. 2004 Oct;36(10):1861-7. doi: 10.1016/j.biocel.2004.02.023. PMID: 15203098.
Allen NJ, Lyons DA. Glia as architects of central nervous system formation and function. Science. 2018 Oct 12;362(6411):181-185. doi: 10.1126/science.aat0473. PMID: 30309945; PMCID: PMC6292669.
Dzamba D, Harantova L, Butenko O, Anderova M. Glial Cells - The Key Elements of Alzheimer´s Disease. Curr Alzheimer Res. 2016;13(8):894-911. doi: 10.2174/1567205013666160129095924. PMID: 26825092.
Seguella L, Gulbransen BD. Enteric glial biology, intercellular signalling and roles in gastrointestinal disease. Nat Rev Gastroenterol Hepatol. 2021 Aug;18(8):571-587. doi: 10.1038/s41575-021-00423-7. Epub 2021 Mar 17. PMID: 33731961; PMCID: PMC8324524.
Kim YS, Choi J, Yoon BE. Neuron-Glia Interactions in Neurodevelopmental Disorders. Cells. 2020 Sep 27;9(10):2176. doi: 10.3390/cells9102176. PMID: 32992620; PMCID: PMC7601502.
Ji RR, Chamessian A, Zhang YQ. Pain regulation by non-neuronal cells and inflammation. Science. 2016 Nov 4;354(6312):572-577. doi: 10.1126/science.aaf8924. PMID: 27811267; PMCID: PMC5488328.
Ji RR, Berta T, Nedergaard M. Glia and pain: is chronic pain a gliopathy? Pain. 2013 Dec;154 Suppl 1(0 1):S10-S28. doi: 10.1016/j.pain.2013.06.022. Epub 2013 Jun 20. PMID: 23792284; PMCID: PMC3858488.
Iyengar S, Johnson KW, Ossipov MH, Aurora SK. CGRP and the Trigeminal System in Migraine. Headache. 2019 May;59(5):659-681. doi: 10.1111/head.13529. Epub 2019 Apr 14. PMID: 30982963; PMCID: PMC6593989.
Ye Y, Salvo E, Romero-Reyes M, Akerman S, Shimizu E, Kobayashi Y, Michot B, Gibbs J. Glia and Orofacial Pain: Progress and Future Directions. Int J Mol Sci. 2021 May 19;22(10):5345. doi: 10.3390/ijms22105345. PMID: 34069553; PMCID: PMC8160907.