PICK1 Regulates the Expression and Trafficking of AMPA Receptors in Remifentanil-Induced Hyperalgesia
PICK1 Regulates the Expression and Trafficking of AMPA Receptors in Remifentanil-Induced Hyperalgesia
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PICK1 调节瑞芬太尼诱导的痛觉过敏中 AMPA 受体的表达和运输
DOI：
10.1213/ane.0000000000001442
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发表时间：
2016-09
影响因子：
5.7
通讯作者：
Wang Guolin
中科院分区：
文献类型：
--
作者：
Wang Zhifen;Yuan Yuan;Xie Keliang;Tang Xiaohong;Zhang Linlin;Ao Jiying;Li Nan;Zhang Yu;Guo Suqian;Wang Guolin
背景技术背景：瑞芬太尼因其较其他阿片类镇痛药诱发痛敏更快、更常见而被广泛应用于临床麻醉。N-甲基-D-天冬氨酸（NMDA）受体的激活在瑞芬太尼引起的痛觉过敏中起关键作用。与NMDA受体一样，β-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）也是突触后膜上的兴奋性谷氨酸受体，参与了急性和慢性疼痛的传递。与C激酶1（PICK 1）相互作用的蛋白质在NMDA受体介导的含谷氨酸受体2（GluR 2）的AMPAR的内化中起重要作用，并有助于诱导和维持炎症诱导的疼痛。本研究旨在验证PICK 1通过调节脊髓中AMPAR的表达和运输参与瑞芬太尼诱导的痛觉过敏的假设。方法：通过静脉输注瑞芬太尼，使用瑞芬太尼诱导的大鼠痛觉过敏模型，我们首先测量了瑞芬太尼输注前24小时和输注后2，6，24和48小时的机械和热痛觉过敏的变化。采用逆转录-定性聚合酶链反应、免疫组化和Western blot检测PICK 1 mRNA和蛋白表达以及AMPAR亚基在脊髓中的表达和运输。此外，我们通过鞘内注射PICK 1反义寡核苷酸来敲低PICK 1的表达，以研究PICK 1缺陷对瑞芬太尼诱导的痛觉过敏以及AMPAR表达和运输的影响。研究结果：对于伤害性阈值（缩爪阈值和缩爪潜伏期;所有P <0.0001），发现显著的时间-组相互作用。瑞芬太尼输注在不同时间点诱导明显的痛觉过敏（P < .0001），PICK 1敲低可部分逆转（P < .007）。此外，瑞芬太尼可增加PICK 1 mRNA和蛋白的表达（P < .0001），并增加脊髓背角神经元膜GluR 1和GluR 2的内化（P < .0011）。更重要的是，PICK 1缺陷可减弱瑞芬太尼诱导的脊髓背角GluR 2内化（P < .01），但对瑞芬太尼诱导的膜GluR 1表达无影响（P ≥ .985）。结论：这些结果表明PICK 1缺陷可能通过调节含GluR 2的AMPAR在脊髓背角的表达和运输来逆转瑞芬太尼诱导的痛觉过敏。
BACKGROUND: Remifentanil is used widely in clinical anesthesia because it induces more rapid and more common hyperalgesia than other opioid analgesics. Activation of N-methyl-D-aspartate (NMDA) receptors takes a pivotal part in remifentanil-induced hyperalgesia. Like NMDA receptors, the &agr;-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are excitatory ion glutamate receptors in postsynaptic membrane, which are involved in the transmission of both acute and chronic pain. Protein interacting with C kinase 1 (PICK1) plays an important role in NMDA receptor-mediated internalization of glutamate receptor 2 (GluR2)-containing AMPARs and contributes to the induction and maintenance of inflammation-induced pain. This study aimed to test the hypothesis that PICK1 contributes to remifentanil-induced hyperalgesia by regulating AMPAR expression and trafficking in the spinal cord. METHODS: Using a rat model of remifentanil-induced hyperalgesia by intravenous infusion of remifentanil, we first measured changes in mechanical and thermal hyperalgesia at 24 hours before remifentanil infusion and 2, 6, 24, and 48 hours after infusion. PICK1 mRNA and protein expression and AMPAR subunit expression and trafficking in the spinal cord were then detected by reverse transcription–qualitative polymerase chain reaction, immunohistochemistry, and Western blot. In addition, we knocked down PICK1 expression by intrathecal administration of PICK1 antisense oligodeoxynucleotide to investigate the effects of PICK1 deficiency on remifentanil-induced hyperalgesia and the expression and trafficking of AMPARs. RESULTS: A significant time–group interaction was found for nociceptive thresholds (paw withdrawal threshold and paw withdrawal latency; all P < .0001). Remifentanil infusion induced distinct hyperalgesia at different time points (P < .0001), which was partly reversed by PICK1 knockdown (P < .007). Besides, remifentanil infusion increased the expression of PICK1 mRNA and protein (P < .0001) and the membrane GluR1 and GluR2 internalization in spinal dorsal horn neurons (P < .0011). More importantly, PICK1 deficiency could attenuate remifentanil-induced GluR2 internalization in the spinal cord dorsal horn (P < .01) but had no effect on remifentanil-induced membrane GluR1 expression (P ≥ .985). CONCLUSIONS: These results indicate that PICK1 deficiency might reverse remifentanil-induced hyperalgesia through regulating GluR2-containing AMPAR expression and trafficking in the spinal cord dorsal horn.
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DOI：
10.1074/jbc.m114.580381
发表时间：
2014-06
期刊：
The Journal of Biological Chemistry
影响因子：
--
作者：
Wenjuan Tao;Quan Chen;Wenjie Zhou;Yunping Wang;Lu Wang;Zhi Zhang
通讯作者：
Wenjuan Tao;Quan Chen;Wenjie Zhou;Yunping Wang;Lu Wang;Zhi Zhang
脊髓α-Amino-3-羟基-5-甲基-4-异恶唑丙酸受体受体的作用在完整的弗朗德辅助引起的炎症性疼痛中。
影响因子：
3.3
作者：
Park JS;Yaster M;Guan X;Xu JT;Shih MH;Guan Y;Raja SN;Tao YX
通讯作者：
Tao YX
富氢盐水通过大鼠 DRG 中的 GSK-3 控制瑞芬太尼诱导的过度伤害感受和 NMDA 受体 NR1 亚基膜运输
影响因子：
3.8
作者：
Linlin Zhang;Ruichen Shu;Haiyun Wang;Guolin Wang
通讯作者：
Guolin Wang
影响因子：
16.2
作者：
Xia, J;Zhang, XQ;Huganir, RL
通讯作者：
Huganir, RL
影响因子：
3.6
作者：
J. R. Sneyd;F. Camu;A. Doenicke;C. Mann;O. Holgersen;J. Helmers;L. Appelgren;D. Noronha;B. Upadhyaya
通讯作者：
J. R. Sneyd;F. Camu;A. Doenicke;C. Mann;O. Holgersen;J. Helmers;L. Appelgren;D. Noronha;B. Upadhyaya