Downregulation of neuroligin1 ameliorates postoperative pain through inhibiting neuroligin1/postsynaptic density 95-mediated synaptic targeting of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor GluA1 subunits in rat dorsal horns.
Downregulation of neuroligin1 ameliorates postoperative pain through inhibiting neuroligin1/postsynaptic density 95-mediated synaptic targeting of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor GluA1 subunits in rat dorsal horns.
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DOI：
10.1177/1744806918766745
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发表时间：
2018-01
期刊：
影响因子：
3.3
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Guo R;Li H;Li X;Xue Z;Sun Y;Ma D;Guan Y;Li J;Tian M;Wang Y
Neuroligin1是一种重要的突触细胞粘附分子，通过蛋白-蛋白相互作用调节突触功能。然而，神经oligin1对脊髓突触传递的调节是否有助于术后疼痛的发生尚不清楚。在大鼠足底术后疼痛模型中，我们采用Western blot方法检测损伤后脊髓背角突触后膜神经胶质素1、突触后密度95 （PSD-95）和α-氨基-3-羟基-5-甲基-4-异唑丙酸（AMPA）受体GluA1和GluA2亚基的表达变化。采用共免疫沉淀法进一步测定了neurorigin1与PSD-95的相互作用。与对照组相比，切口后3 h和1 d同侧背角突触后膜中神经胶质素1和GluA1蛋白水平显著升高，而GluA2和PSD-95蛋白水平未见明显升高（naïve）。切口后3 h PSD-95与神经球蛋白1共免疫沉淀量明显高于对照组。鞘内注射靶向神经胶质素1的小干扰rna （sirna）可抑制脊髓中神经胶质素1的表达。重要的是，鞘内神经胶质素1 siRNA2497预处理，而不是混乱的siRNA或载体，在切口后3小时阻止了GluA1表达的上调，抑制了神经胶质素1/PSD-95相互作用的增强，并减轻了术后疼痛。总之，目前的研究结果表明，下调脊髓神经胶质素1的表达可能通过抑制神经胶质素1/PSD-95的相互作用和GluA1亚基的突触靶向来改善术后疼痛。因此，脊髓神经胶质素1可能是术后疼痛治疗的潜在新靶点。
Neuroligin1 is an important synaptic cell adhesion molecule that modulates the function of synapses through protein–protein interactions. Yet, it remains unclear whether the regulation of synaptic transmission in the spinal cord by neruoligin1 contributes to the development of postoperative pain. In a rat model of postoperative pain induced by plantar incision, we conducted Western blot study to examine changes in the expression of postsynaptic membrane of neuroligin1, postsynaptic density 95 (PSD-95), and α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor GluA1 and GluA2 subunits in the spinal cord dorsal horn after injury. The interaction between neuroligin1 and PSD-95 was further determined by using coimmunoprecipitation. Protein levels of neuroligin1 and GluA1, but not GluA2 and PSD-95, were significantly increased in the postsynaptic membrane of the ipsilateral dorsal horn at 3 h and 1 day after incision, as compared to that in control group (naïve). A greater amount of PSD-95 was coimmunoprecipitated with neuroligin1 at 3 h after incision than that in the control group. Intrathecal administration of small interfering RNAs (siRNAs) targeting neuroligin1 suppressed the expression of neuroligin1 in the spinal cord. Importantly, pretreatment with intrathecal neuroligin1 siRNA2497, but not scrambled siRNA or vehicle, prevented the upregulation of GluA1 expression at 3 h after incision, inhibited the enhanced neuroligin1/PSD-95 interaction, and attenuated postoperative pain. Together, current findings suggest that downregulation of spinal neuroligin1 expression may ameliorate postoperative pain through inhibiting neuroligin1/PSD-95 interaction and synaptic targeting of GluA1 subunit. Accordingly, spinal neuroligin1 may be a potential new target for postoperative pain treatment.
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