Neuron–Glia Signaling in Trigeminal Ganglion: Implications for Migraine Pathology

Abstract

Objective.-The goal of this study was to investigate neuronal-glial cell signaling in trigeminal ganglia under basal and inflammatory conditions using an in vivo model of trigeminal nerve activation.Background.-Activation of trigeminal ganglion nerves and release of calcitonin gene-related peptide (CGRP) are implicated in the pathology of migraine. Cell bodies of trigeminal neurons reside in the ganglion in close association with glial cells. Neuron-glia interactions are involved in all stages of inflammation and pain associated with several central nervous system (CNS) diseases. However, the role of neuron-glia interactions within the trigeminal ganglion under normal and inflammatory conditions is not known.Methods.-Sprague-Dawley rats were utilized to study neuron-glia signaling in the trigeminal ganglion. Initially, True Blue was used as a retrograde tracer to localize neuronal cell bodies in the ganglion by fluorescent microscopy and multiple image alignment. Dye-coupling studies were conducted under basal conditions and in response to capsaicin injection into the TMJ capsule. S100B and p38 expression in neurons and glia were determined by immunohistochemistry following chemical stimulation. CGRP levels in the ganglion were measured by radioimmunoassay in response to capsaicin. In addition, the effect of CGRP on the release of 19 different cytokines from cultured glial cells was investigated by protein microarray analysis.Results.-In unstimulated control animals, True Blue was detected primarily in neuronal cell bodies localized in clusters within the ganglion corresponding to the V3 region (TMJ capsule), V2 region (whisker pad), or V1 region (eyebrow and eye). However, True Blue was detected in both neuronal cell bodies and adjacent glia in the V3 region of the ganglion obtained from animals injected with capsaicin. Dye movement into the surrounding glia correlated with the time after capsaicin injection. Chemical stimulation of V3 trigeminal nerves was found to increase the expression of the inflammatory proteins S100B and p38 in both neurons and glia within the V3 region. Unexpectedly, increased levels of these proteins were also observed in the V2 and V1 regions of the ganglion. CGRP and the vesicle docking protein SNAP-25 were colocalized in many neuronal cell bodies and processes. Decreased CGRP levels in the ganglion were observed 2 hours following capsaicin stimulation. Using protein microarray analysis, CGRP was shown to differentially regulate cytokine secretion from cultured trigeminal ganglion glia.Conclusions.-We demonstrated that activation of trigeminal neurons leads to changes in adjacent glia that involve communication through gap junctions and paracrine signaling. This is the first evidence, to our knowledge, of neuron-glia signaling via gap junctions within the trigeminal ganglion. Based on our findings, it is likely that neuronal-glial communication via gap junctions and paracrine signaling are involved in the development of peripheral sensitization within the trigeminal ganglion and, thu...

Targeting CGRP: A New Era for Migraine Treatment

“…In the periphery, release of CGRP from trigeminal fibers is believed to cause vasodilation and mast cell degranulation, ultimately resulting in a persistent pro-inflammatory sensitization of trigeminal nociceptors [53][54][55]. Studies have suggested that CGRP release works in a paracrine manner, causing excitation of nearby neuronal and satellite glial cells and stimulating its own synthesis [56]. This cascade of events supports the role of CGRP in the development and maintenance of peripheral and central sensitization in migraine pathogenesis [20].…”

Central Sensitization: Clinical Implications for Chronic Head and Neck Pain

“…The resulting depression, anxiety, sleep fragmentation, allodynia, and hyperalgesia characterize a number of chronic pain disorders. [2][3][4][5][6][7][8][9][10][11][12][13] At least two etiological pathways are posited for central sensitization. The first is chronification of nociceptive pain; and involves neuroplastic changes, and peripheral sensitization as precursors to central sensitization and the resulting clinical pain.…”

“…This contributes to the fatigue and malaise often associated with CSS. [5,12,14,20,21,[23][24][25][33][34][35][36][37][38] Utilizing the resultant depression, anxiety, hyperalgesia, allodynia, stress related pain exacerbation, fatigue, and poor sleep, we can establish a list of indicators for central sensitization. Taken alone, with the possible exception of allodynia and stress related pain, none of these are pathognomonic.…”

“…As such, PENS is one of our few cost-effective, non-invasive, low co-morbidity options for the treatment of central sensitization itself, as opposed to responding to the deleterious effects of CS. [1,2,5,6,[8][9][10][12][13][14][15][20][21][22][23][25][26][27][28][42][43][44]53,55] The other broad category of non-pharmaceutical CS intervention encompasses manual therapy, virtual reality, improving stress tolerance, and transcutaneous electric nerve stimulation. These can be thought of as addressing the functional deficits created by the CS.…”

“…[6,[21][22][23][24][25] • Decreased medullary descending inhibition of nociception, This increases the effective peripheral nociceptive input, and is reflected in lowered pain thresholds, hyperalgesia, allodynia, and greater impact of peripheral sensitization. [8,11,12,[15][16][17]23,[26][27][28][29][30][31][32] • Hypoactivity of the hypothalamic-pituitary-adrenal axis, and autonomic nervous system alterations, produce increased sympathetic tone, low vagal tone, and contribute to immune abnormalities. This contributes to the fatigue and malaise often associated with CSS.…”