Differential roles of NMDAR subunits 2A and 2B in mediating peripheral and central sensitization contributing to orofacial neuropathic pain
Differential roles of NMDAR subunits 2A and 2B in mediating peripheral and central sensitization contributing to orofacial neuropathic pain
复制标题
NMDAR 亚基 2A 和 2B 在介导导致口面部神经病理性疼痛的外周和中枢敏化中的不同作用
DOI：
10.1016/j.bbi.2022.08.010
复制
发表时间：
2022-08-30
影响因子：
15.1
通讯作者：
Shen，Jie-Fei
中科院分区：
文献类型：
--
作者：
Zhang，Yan-Yan;Liu，Fei;Shen，Jie-Fei
脊髓N-甲基-d-天冬氨酸受体（NMDAR），特别是其亚型NR 2A和NR 2B，在神经病理性疼痛和炎性疼痛中起关键作用。然而，NR 2A和NR 2B在口面疼痛中的作用以及介导神经系统敏化的确切分子和细胞机制仍然知之甚少。在这里，我们详尽地评估了NMDAR在介导口面神经性疼痛的外周和中枢敏化中的调节作用。Von-Frey细丝法显示下牙槽神经切断（IANX）可引起小鼠须垫异位痛觉超敏行为。有趣的是，在缺乏NR 2A和NR 2B的小鼠中，机械性异常性疼痛被逆转。IANX还促进外周致敏相关分子的产生，如白细胞介素（IL）-1β、肿瘤坏死因子（TNF）-α、脑源性神经营养因子（BDNF）和趋化因子上调（C单键C基序）配体2（CCL 2），并降低三叉神经节胶质细胞上的内向钾通道（Kir）4.1，但NR 2A条件性敲除（CKO）小鼠阻止了这些变化。而NR 2B CKO仅阻断了Kir4.1、IL-1β和TNF-α的变化，并进一步促进了CCL 2的产生。IANX可促进三叉神经尾状脊束核中与中枢致敏相关的c-fos、胶质细胞酸性蛋白（GFAP）和离子化钙结合适配分子1（Iba-1）的表达，并降低Kir4.1的表达。此外，还观察到NR 2A和NR 2B在介导中枢敏化中的不同作用。沉默NR 2B可有效降低c-fos、GFAP和Iba-1，但不影响Kir4.1。相反，NR 2A CKO仅改变Iba-1和Kir4.1，并进一步增加c-fos和GFAP。功能获得和功能丧失的方法提供了对NR 2A和NR 2B在介导由IANX诱导的外周和中枢伤害性敏化中的不同作用的洞察，这可能是推进神经机制对神经损伤的反应的知识的基本基础。
The spinalN-methyl-d-aspartate receptor (NMDAR), particularly their subtypes NR2A and NR2B, plays pivotal roles in neuropathic and inflammatory pain. However, the roles of NR2A and NR2B in orofacial pain and the exact molecular and cellular mechanisms mediating nervous system sensitization are still poorly understood. Here, we exhaustively assessed the regulatory effect of NMDAR in mediating peripheral and central sensitization in orofacial neuropathic pain. Von-Frey filament tests showed that the inferior alveolar nerve transection (IANX) induced ectopic allodynia behavior in the whisker pad of mice. Interestingly, mechanical allodynia was reversed in mice lacking NR2A and NR2B. IANX also promoted the production of peripheral sensitization-related molecules, such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, brain-derived neurotrophic factor (BDNF), and chemokine upregulation (Csingle bondC motif) ligand 2 (CCL2), and decreased the inward potassium channel (Kir) 4.1 on glial cells in the trigeminal ganglion, but NR2A conditional knockout (CKO) mice prevented these alterations. In contrast, NR2B CKO only blocked the changes of Kir4.1, IL-1β, and TNF-α and further promoted the production of CCL2. Central sensitization-related c-fos, glial fibrillary acidic protein (GFAP), and ionized calcium-binding adaptor molecule 1 (Iba-1) were promoted and Kir4.1 was reduced in the spinal trigeminal caudate nucleus by IANX. Differential actions of NR2A and NR2B in mediating central sensitization were also observed. Silencing of NR2B was effective in reducing c-fos, GFAP, and Iba-1 but did not affect Kir4.1. In contrast, NR2A CKO only altered Iba-1 and Kir4.1 and further increased c-fos and GFAP. Gain-of-function and loss-of-function approaches provided insight into the differential roles of NR2A and NR2B in mediating peripheral and central nociceptive sensitization induced by IANX, which may be a fundamental basis for advancing knowledge of the neural mechanisms’ reaction to nerve injury.