Activation of α2 adrenoceptors inhibited NMDA receptor-mediated nociceptive transmission in spinal dorsal horn of mice with inflammatory pain
Activation of α2 adrenoceptors inhibited NMDA receptor-mediated nociceptive transmission in spinal dorsal horn of mice with inflammatory pain
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α2 肾上腺素受体的激活抑制炎性疼痛小鼠脊髓背角 NMDA 受体介导的伤害性传递
DOI：
10.1016/j.neuropharm.2013.09.024
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发表时间：
2014-02-01
影响因子：
4.7
通讯作者：
Hu, Xiao-Dong
中科院分区：
文献类型：
--
作者：
Fan, Qing-Qing;Li, Lu;Hu, Xiao-Dong
α2肾上腺素能受体在脊髓背角中高度丰富，参与了去甲肾上腺素能下行痛觉的调节。在周围组织损伤后，鞘内应用α2肾上腺素能受体激动剂有效地减轻病理性疼痛超敏反应，尽管确切的机制尚不完全清楚。本研究通过足底注射完全弗氏佐剂(CFA)诱导炎性痛，并制备脊髓切片，观察α2肾上腺素能受体激动剂可乐定对脊髓敏化的关键分子NMDAR介导的突触传递的可能影响。全细胞膜片钳记录显示可乐定通过激活α2A型肾上腺素受体显著降低炎症小鼠NMDAR介导的单突触反应的幅度。应用可乐定前后配对脉搏比无明显变化，提示突触后起源。细胞内非水解性GDP类似物GDPβ-S可阻断可乐定对NMDAR电流的抑制作用，而直接抑制cAMP依赖的蛋白激酶类似于可乐定对NMDAR电流的抑制作用，提示GαI蛋白/PKA信号通路参与了可乐定的作用。体内生化分析显示，鞘内注射可乐定后，突触体膜GluN2B亚基NMDAR的含量明显降低，这与其减轻炎性疼痛密切相关。体外电生理记录进一步证明，GluN2B受体选择性抑制剂ifenprodil显著降低炎症小鼠的NMDAR突触反应，更重要的是，阻断了可乐定产生的突触抑制。提示去甲肾上腺素对炎性痛的抑制作用可能与阻断GluN2B受体介导的脊髓背角伤害性传递有关。(C)2013爱思唯尔有限公司。保留所有权利。
The (alpha 2 adrenoceptor is highly enriched in spinal dorsal horn and involved in descending noradrenergic pain modification. Following peripheral tissue injury, intrathecal application of alpha 2 adrenoceptor agonists effectively alleviates the pathological pain hypersensitivity, although the precise mechanisms are not fully understood. The present study induced inflammatory pain by intraplantar injection of Complete Freund's Adjuvant (CFA), and prepared the spinal cord slices to assay the possible influence of alpha 2 adrenoceptor agonist clonidine on the synaptic transmission mediated by NMDA receptor (NMDAR), a critical player in spinal sensitization. Whole-cell patch clamp recordings in lamina II neurons illustrated that clonidine significantly decreased the amplitudes of NMDAR-mediated monosynaptic responses in inflamed mice through activation of alpha 2A-subtype adrenoceptor. No significant alteration in the paired-pulse ratio before and after clonidine application indicated the postsynaptic origin. Intracellular loading of nonhydrolyzable GDP analog GDP-beta-S blocked, whereas direct inhibition of cAMP-dependent protein kinase (PKA) mimicked, the inhibitory effect of clonidine on NMDAR currents, implicating that G alpha i protein/PKA signaling was involved in clonidine action. Biochemical analysis in vivo revealed that intrathecal clonidine administration specifically decreased the content of GluN2B subunit-containing NMDAR at synaptosomal membrane fraction, a result associated closely with the alleviation of inflammatory pain. Electrophysiological recordings in vitro further demonstrated that GluN2B receptor-selective inhibitor ifenprodil dramatically reduced NMDAR synaptic responses in inflamed mice and more importantly, occluded the synaptic inhibition produced by clonidine. These data suggested that the noradrenergic suppression of inflammatory pain might involve the blockade of GluN2B receptor-mediated nociceptive transmission in spinal dorsal horn. (C) 2013 Elsevier Ltd. All rights reserved.