Department of Stomatognathic Function and Occlusal Reconstruction, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8504, Japan.
Department of Oral Molecular Pathology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8504, Japan.
Int J Mol Sci. 2019 Feb 7;20(3):711. doi: 10.3390/ijms20030711.
Neuron-glia interactions contribute to pain initiation and sustainment. Intra-ganglionic (IG) secretion of calcitonin gene-related peptide (CGRP) in the trigeminal ganglion (TG) modulates pain transmission through neuron-glia signaling, contributing to various orofacial pain conditions. The present study aimed to investigate the role of satellite glial cells (SGC) in TG in causing cytokine-related orofacial nociception in response to IG administration of CGRP. For that purpose, CGRP alone (10 μL of 10 M), Minocycline (5 μL containing 10 μg) followed by CGRP with one hour gap (Min + CGRP) were administered directly inside the TG in independent experiments. Rats were evaluated for thermal hyperalgesia at 6 and 24 h post-injection using an operant orofacial pain assessment device (OPAD) at three temperatures (37, 45 and 10 °C). Quantitative real-time PCR was performed to evaluate the mRNA expression of IL-1β, IL-6, TNF-α, IL-1 receptor antagonist (IL-1RA), sodium channel 1.7 (NaV 1.7, for assessment of neuronal activation) and glial fibrillary acidic protein (GFAP, a marker of glial activation). The cytokines released in culture media from purified glial cells were evaluated using antibody cytokine array. IG CGRP caused heat hyperalgesia between 6⁻24 h (paired- test, < 0.05). Between 1 to 6 h the mRNA and protein expressions of GFAP was increased in parallel with an increase in the mRNA expression of pro-inflammatory cytokines IL-1β and anti-inflammatory cytokine IL-1RA and NaV1.7 (one-way ANOVA followed by Dunnett's post hoc test, < 0.05). To investigate whether glial inhibition is useful to prevent nociception symptoms, Minocycline (glial inhibitor) was administered IG 1 h before CGRP injection. Minocycline reversed CGRP-induced thermal nociception, glial activity, and down-regulated IL-1β and IL-6 cytokines significantly at 6 h (-test, < 0.05). Purified glial cells in culture showed an increase in release of 20 cytokines after stimulation with CGRP. Our findings demonstrate that SGCs in the sensory ganglia contribute to the occurrence of pain via cytokine expression and that glial inhibition can effectively control the development of nociception.
神经元-胶质细胞相互作用促进疼痛的起始和维持。三叉神经节（TG）中的神经节内（IG）降钙素基因相关肽（CGRP）的分泌通过神经元-胶质细胞信号调节疼痛传递，导致各种口腔面部疼痛状况。本研究旨在探讨 TG 中卫星胶质细胞（SGC）在 CGRPIG 给药引起细胞因子相关口腔痛觉过敏中的作用。为此，在独立实验中单独给予 CGRP（10μL 10M），米诺环素（5μL 含 10μg），然后 CGRP 间隔一小时（Min+CGRP）。使用操作式口腔疼痛评估装置（OPAD）在三个温度（37、45 和 10°C）下，在注射后 6 和 24 小时评估大鼠的热痛觉过敏。进行实时定量 PCR 以评估白细胞介素 1β（IL-1β）、白细胞介素 6（IL-6）、肿瘤坏死因子-α（TNF-α）、白细胞介素 1 受体拮抗剂（IL-1RA）、钠通道 1.7（NaV1.7，用于评估神经元激活）和神经胶质纤维酸性蛋白（GFAP，胶质激活标志物）的 mRNA 表达。使用抗体细胞因子阵列评估从纯化的神经胶质细胞中释放的细胞因子。IG CGRP 在 6⁻24 小时之间引起热痛觉过敏（配对检验， < 0.05）。在 1 至 6 小时之间，GFAP 的 mRNA 和蛋白表达与促炎细胞因子 IL-1β和抗炎细胞因子 IL-1RA 和 NaV1.7 的 mRNA 表达增加平行增加（单因素方差分析后进行 Dunnett 事后检验， < 0.05）。为了研究胶质抑制是否有助于预防疼痛症状，米诺环素（胶质抑制剂）在 CGRP 注射前 1 小时 IG 给药。米诺环素逆转了 CGRP 诱导的热痛觉过敏，在 6 小时时显著下调了 GFAP 活性和 IL-1β 和 IL-6 细胞因子（-检验， < 0.05）。经刺激后，培养的纯化神经胶质细胞中 20 种细胞因子的释放增加了 CGRP。我们的研究结果表明，感觉神经节中的 SGC 通过细胞因子表达促进疼痛的发生，胶质抑制可有效控制痛觉过敏的发展。
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