SCS通过诱导脊髓小胶质细胞M2极化并释放TGF-β调控疼痛阈值的研究

Spinal cord stimulation upregulated mechanical threshold via inducing the spinal microglia into M2 polarization and TGF-β release

摘要:

【摘 要】目的：探讨脊髓电刺激（SCS）治疗慢性疼痛的神经免疫机制。方法：在Na?ve小鼠中植入电极，进行连续脊髓电刺激，观察机械痛阈值的改变和脊髓中小胶质细胞的极化状态。并测定脊髓和脑脊液中TGF-β的表达水平，和抑制TGF-β功能后SCS对机械痛阈改变的影响。结果：电极植入术未改变小鼠的机械痛阈值和运动能力。连续SCS显著提高小鼠的机械痛阈，增加脊髓背角中小胶质细胞M2极化水平和TGF-β的表达，鞘内注射TGF-β抗体减弱SCS对机械痛阈值的影响。结论：连续的脊髓电刺激通过激活脊髓小胶质细胞并使其进入M2极化状态，释放TGF-β，进而上调疼痛阈值发挥镇痛作用。

Abstract:

【Abstract】 Objective: To investigate the central mechanism of spinal cord stimulation (SCS) for the treatment of chronic pain. Methods: SCS electrodes were implanted in the subarachnoid space of Na?ve mice, and spinal cord stimulation was performed for 7 consecutive days (frequency 50 Hz; pulse width 200 μs; intensity 80% MoT; duration 30 min), and the mechanical pain threshold was observed. The expression and ratio changes of Iba1 and Arg1 in the spinal cord after continuous SCS were detected to determine the polarisation status of microglia. The expression of TGF-β in the spinal cord and cerebrospinal fluid was determined by immunoblotting and ELISA, respectively. Finally, intrathecal injection of TGF-β1 neutralising antibody was used to observe its effect on SCS-induced changes in mechanical pain threshold. Results:Implantation of SCS electrodes did not alter the mechanical pain threshold and locomotor ability of mice. Continuous SCS significantly increased the mechanical pain threshold of mice compared with the sham-stimulation group (no stimulation and only implantation of SCS electrodes).SCS significantly increased the protein expression of Iba1 and Arg1 in the dorsal horn of the spinal cord and the ratio of Arg1 to Iba1.SCS increased the expression of TGF-β in the spinal cord or cerebrospinal fluid, and intrathecal injection of antibodies against TGF-β attenuated the effect of SCS on the mechanical pain threshold. Conclusion: Consecutive spinal cord stimulation upregulates the pain threshold by activating the spinal microglia to enter a state of M2 polarization which in turn releases TGF-β.