The crucial role of NR2A mediating the activation of satellite glial cells in the trigeminal ganglion contributes to orofacial inflammatory pain during TMJ inflammation

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology Pub Date : 2024-09-30 DOI:10.1016/j.neuropharm.2024.110173

Qin-Xuan Song , Yan-Yan Zhang , Yue-Ling Li , Fei Liu , Ya-Jing Liu , Yi-Ke Li , Chun-jie Li , Cheng Zhou , Jie-Fei Shen

{"title":"The crucial role of NR2A mediating the activation of satellite glial cells in the trigeminal ganglion contributes to orofacial inflammatory pain during TMJ inflammation","authors":"Qin-Xuan Song , Yan-Yan Zhang , Yue-Ling Li , Fei Liu , Ya-Jing Liu , Yi-Ke Li , Chun-jie Li , Cheng Zhou , Jie-Fei Shen","doi":"10.1016/j.neuropharm.2024.110173","DOIUrl":null,"url":null,"abstract":"<div><div>Temporomandibular joint inflammatory diseases are a significant subtype of temporomandibular disorders (TMD) characterized by inflammatory pain in the orofacial area. The N-methyl-D-aspartate receptor (NMDAR), specifically the NR2A subtype, was crucial in neuropathic pain. However, the exact role of NR2A in inflammatory pain in the TMJ and the molecular and cellular mechanisms mediating peripheral sensitization in the trigeminal ganglion (TG) remain unclear. This study utilized male and female mice to induce the TMJOA model by injecting Complete Freund's adjuvant (CFA) into the TMJ and achieve conditional knockout (CKO) of NR2A in the TG using Cre/Loxp technology. The Von-Frey filament test results showed that CFA-induced orofacial pain with reduced mechanical withdrawal threshold (MWT), which was not developed in NR2A CKO mice. Additionally, the up-regulation of interleukin (IL)-1β, IL-6, and nerve growth factor (NGF) in the TG induced by CFA did not occur by NR2A deficiency. In vitro, NMDA activated satellite glial cells (SGCs) with high expression of glial fibrillary acidic protein (GFAP), and both NMDA and LPS led to increased IL-1β, IL-6, and NGF in SGCs. NR2A deficiency reduced these stimulating effects of NMDA and LPS. The regulation of IL-1β involved the p38, Protein Kinase A (PKA), and Protein Kinase C (PKC) pathways, while IL-6 signaling relied on PKA and PKC pathways. NGF regulation was primarily through the p38 pathway. This study highlighted NR2A's crucial role in the TG peripheral sensitization during TMJ inflammation by mediating ILs and NGF, suggesting potential targets for orofacial inflammatory pain management.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"261 ","pages":"Article 110173"},"PeriodicalIF":4.6000,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neuropharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0028390824003423","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}

引用次数: 0

Abstract

Temporomandibular joint inflammatory diseases are a significant subtype of temporomandibular disorders (TMD) characterized by inflammatory pain in the orofacial area. The N-methyl-D-aspartate receptor (NMDAR), specifically the NR2A subtype, was crucial in neuropathic pain. However, the exact role of NR2A in inflammatory pain in the TMJ and the molecular and cellular mechanisms mediating peripheral sensitization in the trigeminal ganglion (TG) remain unclear. This study utilized male and female mice to induce the TMJOA model by injecting Complete Freund's adjuvant (CFA) into the TMJ and achieve conditional knockout (CKO) of NR2A in the TG using Cre/Loxp technology. The Von-Frey filament test results showed that CFA-induced orofacial pain with reduced mechanical withdrawal threshold (MWT), which was not developed in NR2A CKO mice. Additionally, the up-regulation of interleukin (IL)-1β, IL-6, and nerve growth factor (NGF) in the TG induced by CFA did not occur by NR2A deficiency. In vitro, NMDA activated satellite glial cells (SGCs) with high expression of glial fibrillary acidic protein (GFAP), and both NMDA and LPS led to increased IL-1β, IL-6, and NGF in SGCs. NR2A deficiency reduced these stimulating effects of NMDA and LPS. The regulation of IL-1β involved the p38, Protein Kinase A (PKA), and Protein Kinase C (PKC) pathways, while IL-6 signaling relied on PKA and PKC pathways. NGF regulation was primarily through the p38 pathway. This study highlighted NR2A's crucial role in the TG peripheral sensitization during TMJ inflammation by mediating ILs and NGF, suggesting potential targets for orofacial inflammatory pain management.

查看原文本刊更多论文

NR2A 在三叉神经节卫星神经胶质细胞的激活过程中起着至关重要的作用，它是颞下颌关节炎期间口面部炎性疼痛的原因之一。

颞下颌关节炎性疾病是颞下颌关节紊乱症（TMD）的一个重要亚型，其特征是口面部区域的炎性疼痛。N-甲基-D-天冬氨酸受体（NMDAR），特别是 NR2A 亚型，在神经病理性疼痛中至关重要。然而，NR2A 在颞下颌关节炎性疼痛中的确切作用以及介导三叉神经节（TG）外周敏化的分子和细胞机制仍不清楚。本研究利用雌雄小鼠，通过向颞下颌关节注射完全弗氏佐剂（CFA）诱导颞下颌关节疼痛模型，并利用 Cre/Loxp 技术在三叉神经节中实现 NR2A 的条件性基因敲除（CKO）。Von-Frey丝试验结果表明，CFA诱发的口面部疼痛会降低机械退缩阈值（MWT），而NR2A CKO小鼠不会出现这种情况。此外，白细胞介素（IL）-1β、IL-6和神经生长因子（NGF）在CFA诱导的TG中的上调不会因NR2A缺乏而发生。在体外，NMDA 激活了神经胶质纤维酸性蛋白（GFAP）高表达的卫星神经胶质细胞（SGCs），NMDA 和 LPS 均导致卫星神经胶质细胞中的 IL-1β、IL-6 和 NGF 增加。NR2A 缺乏会降低 NMDA 和 LPS 的刺激作用。IL-1β的调节涉及p38、蛋白激酶A（PKA）和蛋白激酶C（PKC）途径，而IL-6的信号传导则依赖于PKA和PKC途径。NGF 主要通过 p38 通路进行调节。这项研究强调了 NR2A 通过介导 ILs 和 NGF 在颞下颌关节炎症期间对 TG 外周敏感性的关键作用，为口腔炎症性疼痛的治疗提供了潜在靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Neuropharmacology 医学-神经科学

CiteScore

10.00

自引率

4.30%

发文量

288

审稿时长

45 days

期刊介绍： Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).