Spinal Protein Kinase Mζ Regulates α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor Trafficking and Dendritic Spine Plasticity via Kalirin-7 in the Pathogenesis of Remifentanil-induced Postincisional Hyperalgesia in Rats
Spinal Protein Kinase Mζ Regulates α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor Trafficking and Dendritic Spine Plasticity via Kalirin-7 in the Pathogenesis of Remifentanil-induced Postincisional Hyperalgesia in Rats
复制标题
脊髓蛋白激酶 Mzeta 在瑞芬太尼诱导的大鼠切口后痛觉过敏的发病机制中通过 Kalirin-7 调节 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体运输和树突脊柱可塑性。
DOI：
10.1097/aln.0000000000002190
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发表时间：
2018-07-01
期刊：
影响因子：
8.8
通讯作者：
Wang, Guolin
中科院分区：
文献类型：
--
作者：
Zhang, Linlin;Guo, Suqian;Wang, Guolin
背景：术中瑞芬太尼麻醉会加重术后疼痛敏感性。最近的研究总结了蛋白激酶mzeta在α -氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体介导的病理性疼痛中的意义。鸟嘌呤核苷酸交换因子Kalirin-7，协调AMPA受体的运输和树突脊柱的可塑性。本研究探讨了蛋白激酶mzeta和Kalirin-7是否通过AMPA受体参与瑞芬太尼诱导的切口后痛觉过敏。方法：瑞芬太尼输注1 μ g后10 min行足底切开。Kg (-1) min（-1为60分钟）。评估足爪戒断阈值（主要结局）、脊髓蛋白激酶M zeta活性、Kalirin-7表达、AMPA受体转运和脊柱形态。蛋白激酶mzeta抑制剂和短发夹RNA敲低Kalirin-7阐明了痛觉过敏的机制和预防。全细胞膜片钳记录分析了蛋白激酶mzeta在脊髓AMPA受体诱导电流中的作用。结果：瑞芬太尼在术后48小时降低了切后足部戒断阈值（平均SD，对照与痛觉过敏，18.9 +/- 1.6 vs. 5.3 +/- 1.2g, n = 7），并伴有脊髓蛋白激酶M zeta磷酸化（97.8 +/- 25.1 vs. 181.5 +/- 18.3%, n = 4）， Kalirin-7生成（101.9 +/- 29.1 vs. 371.2 +/- 59.1%, n = 4）和棘数/10 μ M （2.0 +/- 0.3 vs. 13.0 +/- 1.6, n = 4）的增加。蛋白激酶mzeta抑制剂降低瑞芬太尼诱导的痛觉过敏、Kalirin-7表达和GluA1转运。用蛋白激酶M抑制剂孵育逆转瑞芬太尼增强的AMPA受体诱导的背角神经元电流。加里林-7缺乏损害瑞芬太尼引起的痛觉过敏、突触后GluA1插入和脊柱可塑性。选择性缺乏gla2的AMPA受体拮抗剂以剂量依赖性的方式预防痛觉过敏。结论：脊髓蛋白激酶mzeta通过Kalirin-7过表达调控含glua1的AMPA受体转运和脊柱形态是瑞芬太尼致大鼠痛觉过敏的根本发病机制。
Background: Intraoperative remifentanil anesthesia exaggerates postoperative pain sensitivity. Recent studies recapitulate the significance of protein kinase M zeta in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated pathologic pain. Kalirin-7, a Rho guanine nucleotide exchange factor, coordinates AMPA receptor trafficking and dendritic spine plasticity. This study examines whether protein kinase M zeta and Kalirin-7 contribute to remifentanil-induced postincisional hyperalgesia via AMPA receptor.Methods: Plantar incision was performed 10 min after the start of remifentanil infusion (1 mu g . kg(-1) min(-1) for 60 min). Paw withdrawal threshold (primary outcome), spinal protein kinase M zeta activity, Kalirin-7 expression, AMPA receptor trafficking, and spine morphology were assessed. Protein kinase M zeta inhibitor and Kalirin-7 knockdown by short hairpin RNA elucidated the mechanism and prevention of hyperalgesia. Whole-cell patch-clamp recording analyzed the role of protein kinase M zeta in spinal AMPA receptor-induced current.Results: Remifentanil reduced postincisional paw withdrawal threshold (mean SD, control vs. hyperalgesia, 18.9 +/- 1.6 vs. 5.3 +/- 1.2g, n = 7) at postoperative 48h, which was accompanied by an increase in spinal protein kinase M zeta phosphorylation (97.8 +/- 25.1 vs. 181.5 +/- 18.3%, n = 4), Kalirin-7 production (101.9 +/- 29.1 vs. 371.2 +/- 59.1%, n = 4), and number of spines/10 mu m (2.0 +/- 0.3 vs. 13.0 +/- 1.6, n = 4). Protein kinase M zeta inhibitor reduced remifentanil-induced hyperalgesia, Kalirin-7 expression, and GluA1 trafficking. Incubation with protein kinase M inhibitor reversed remifentanil-enhanced AMPA receptor-induced current in dorsal horn neurons. Kalirin-7 deficiency impaired remifentanil-caused hyperalgesia, postsynaptic GluA1 insertion, and spine plasticity. Selective GluA2-lacking AMPA receptor antagonist prevented hyperalgesia in a dose-dependent manner.Conclusions: Spinal protein kinase M zeta regulation of GluA1-containing AMPA receptor trafficking and spine morphology via Kalirin-7 overexpression is a fundamental pathogenesis of remifentanil-induced hyperalgesia in rats.