Dexmedetomidine attenuates persistent postsurgical pain by upregulating K(+)-Cl(-) cotransporter-2 in the spinal dorsal horn in rats.
Dexmedetomidine attenuates persistent postsurgical pain by upregulating K(+)-Cl(-) cotransporter-2 in the spinal dorsal horn in rats.
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DOI：
10.2147/jpr.s158737
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发表时间：
2018
影响因子：
2.7
通讯作者：
Ma Z
中科院分区：
文献类型：
--
作者：
Dai S;Qi Y;Fu J;Li N;Zhang X;Zhang J;Zhang W;Xu H;Zhou H;Ma Z
右美托咪定（DEX）可能通过调节脑源性神经营养因子（BDNF）发挥镇痛作用。此外，KCC 2诱导的神经元Cl−稳态变化对于GABAA受体介导的突触后抑制至关重要。越来越多的证据表明，神经损伤、外周炎症和应激等因素激活脊髓BDNF/TrkB信号，导致KCC 2转运和表达下调，最终导致GABA能去抑制和痛觉过敏。本实验旨在从分子水平探讨DEX和KCC 2在大鼠持续性术后疼痛（PPSP）中的相互作用。用皮肤/肌肉切开牵拉法（SMIR）诱发大鼠PPSP。使用动态足底感觉计评估机械超敏反应。Western blot和免疫荧光法检测相关蛋白的表达。在我们实验的第一部分中，结果表明，BDNF/TrkB-KCC 2信号在SMIR诱发的PPSP的发生中发挥着关键作用;第二部分表明，在术前15分钟和术后1至3天腹腔内注射40 µg/kg DEX可显着减弱SMIR诱发的PPSP。同时，SMIR诱导的KCC 2下调被部分逆转，这与脊髓背角BDNF/TrkB信号的抑制相一致。此外，鞘内注射KCC 2抑制剂VU 0240551显著降低DEX对SMIR诱发的PPSP的镇痛作用。我们的研究结果表明，DEX通过减少大鼠脊髓背角BDNF/TrkB信号恢复KCC 2功能来减轻PPSP，这为临床手术后疼痛管理提供了治疗慢性疼痛的新见解。
Dexmedetomidine (DEX) could have an analgesic effect on pain transmission through the modulation of brain-derived neurotrophic factor (BDNF). In addition, KCC2-induced shift in neuronal Cl− homeostasis is crucial for postsynaptic inhibition mediated by GABAA receptors. Accumulating evidence shows that nerve injury, peripheral inflammation and stress activate the spinal BDNF/TrkB signal, which results in the downregulation of KCC2 transport and expression, eventually leads to GAGAergic disinhibition and hyperalgesia. The aim of this experiment was to explore the interaction between DEX and KCC2 at a molecular level in rats in the persistent postsurgical pain (PPSP). PPSP in rats was evoked by the skin/muscle incision and retraction (SMIR). Mechanical hypersensitivity was assessed with the Dynamic Plantar Aesthesiometer. Western blot and immunofluorescence assay were used to assess the expressions of related proteins. In the first part of our experiment, the results revealed that the BDNF/TrkB-KCC2 signal plays a critical role in the development of SMIR-evoked PPSP; the second part showed that intraperitoneal administrations of 40 µg/kg DEX at 15 min presurgery and 1 to 3 days post-surgery significantly attenuated SMIR-evoked PPSP. Simultaneously, SMIR-induced KCC2 downregulation was partly reversed, which coincided with the inhibition of the BDNF/TrkB signal in the spinal dorsal horn. Moreover, intrathecal administrations of KCC2 inhibitor VU0240551 significantly reduced the analgesic effect of DEX on SMIR-evoked PPSP. The results of our study indicated that DEX attenuated PPSP by restoring KCC2 function through reducing BDNF/TrkB signal in the spinal dorsal horn in rats, which provides a new insight into the treatment of chronic pain in clinical postsurgical pain management.