Islet-cell autoantigen 69 mediates the antihyperalgesic effects of electroacupuncture on inflammatory pain by regulating spinal glutamate receptor subunit 2 phosphorylation through protein interacting with C-kinase 1 in mice
Islet-cell autoantigen 69 mediates the antihyperalgesic effects of electroacupuncture on inflammatory pain by regulating spinal glutamate receptor subunit 2 phosphorylation through protein interacting with C-kinase 1 in mice
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小鼠体内胰岛细胞自身抗原 69 通过与 C 激酶 1 相互作用的蛋白质调节脊髓谷氨酸受体亚基 2 磷酸化，介导电针对炎性疼痛的抗痛觉过敏作用
DOI：
10.1097/j.pain.0000000000001450
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发表时间：
2019-03-01
期刊：
影响因子：
7.4
通讯作者：
Wang, Junlu
中科院分区：
文献类型：
--
作者：
Han, Kunyuan;Zhang, Anqi;Wang, Junlu
摘要电针在临床上被广泛应用于减轻炎症性疼痛。胰岛细胞自身抗原69（ICA 69）已被报道可调节小鼠的持久痛觉过敏。ICA 69基因敲除导致脊髓背角中与C-激酶1（PICK 1）相互作用的蛋白表达减少，谷氨酸受体亚基2（GluR 2）在Ser 880处磷酸化增加。本研究旨在探讨ICA 69在电针抗痛敏中的作用及其通过调节脊髓背角GluR 2和PICK 1表达的机制。通过皮下足底注射完全弗氏佐剂（CFA）诱导小鼠产生痛觉过敏以引起炎性疼痛。CFA注射后，每隔一天进行电针30分钟。与CFA组相比，CFA+EA组的缩爪频率明显降低。CFA+EA组大鼠同侧海马区ICA 1 mRNA表达和ICA 69蛋白水平显著升高。ICA 69表达在第3天左右达到峰值。更重要的是，ICA 69缺失削弱了EA对GluR 2-p的抗痛敏作用，而PICK 1缺失则没有。将ICA 69肽注入ICA 69基因敲除小鼠的鞘内，可模拟电针镇痛作用，并抑制GluR 2-p。电针对PICK 1和GluR 2的总蛋白没有影响。EA可增加ICA 69-PICK 1复合物的形成，减少PICK 1-GluR 2复合物的形成。我们的研究结果表明，ICA 69介导EA对CFA诱导的炎性疼痛的抗痛觉过敏作用，通过调节脊髓谷氨酸受体2通过PICK 1在小鼠。
Abstract Electroacupuncture (EA) is widely used in clinical settings to reduce inflammatory pain. Islet-cell autoantigen 69 (ICA69) has been reported to regulate long-lasting hyperalgesia in mice. ICA69 knockout led to reduced protein interacting with C-kinase 1 (PICK1) expression and increased glutamate receptor subunit 2 (GluR2) phosphorylation at Ser880 in spinal dorsal horn. In this study, we evaluated the role of ICA69 in the antihyperalgesic effects of EA and the underlying mechanism through regulation of GluR2 and PICK1 in spinal dorsal horn. Hyperalgesia was induced in mice with subcutaneous plantar injection of complete Freund adjuvant (CFA) to cause inflammatory pain. Electroacupuncture was then applied for 30 minutes every other day after CFA injection. When compared with CFA group, paw withdrawal frequency of CFA+EA group was significantly decreased. Remarkable increases in Ica1 mRNA expression and ICA69 protein levels on the ipsilateral side were detected in the CFA+EA group. ICA69 expression reached the peak value around day 3. More importantly, ICA69 deletion impaired the antihyperalgesic effects of EA on GluR2-p, but PICK1 deletion could not. Injecting ICA69 peptide into the intrathecal space of ICA69-knockout mice mimicked the effects of EA analgesic and inhibited GluR2-p. Electroacupuncture had no effects on the total protein of PICK1 and GluR2. And, EA could increase the formation of ICA69-PICK1 complexes and decrease the amount of PICK1-GluR2 complexes. Our findings indicate that ICA69 mediates the antihyperalgesic effects of EA on CFA-induced inflammatory pain by regulating spinal GluR2 through PICK1 in mice.