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κ-阿片受体激动剂U50488H通过Ca/CaMKII/CREB通路改善大鼠神经性疼痛。

The κ-Opioid Receptor Agonist U50488H Ameliorates Neuropathic Pain Through the Ca/CaMKII/CREB Pathway in Rats.

作者信息

Zhang Xiao-Min, Lun Ming-Hui, Du Wei, Ma Fang, Huang Ze-Qing

机构信息

Department of Anesthesiology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institution, NO.44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning Province, 110042, People's Republic of China.

出版信息

J Inflamm Res. 2022 May 23;15:3039-3051. doi: 10.2147/JIR.S327234. eCollection 2022.

DOI:10.2147/JIR.S327234
PMID:35645576
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9140919/
Abstract

OBJECTIVE

To observe the ameliorative effect of kappa opioid receptor (KOR) agonist on rats with neuropathic pain (NP) and investigate the mechanism of action of the calcium ion (Ca)/calcium/calmodulin-dependent protein kinase II (CaMKII)/cyclic AMP response element-binding protein (CREB) pathway.

METHODS

A total of 40 Sprague Dawley rats were randomly divided into four groups: sham-operation group (Sham group), NP model group (NP group), NP + KOR agonist U50488H group (NU group) and NP + specific CaMKII antagonist (KN93) + U50488H group (NKU group). The thermal withdrawal latency (TWL) and mechanical withdrawal threshold (MWT) of each group of rats were determined. ELISA was applied to examine the changes in inflammatory factors and oxidative stress factors, and the apoptotic rate in dorsal root ganglia was observed using TUNEL staining. Ca concentration, content of oxidative stress index ROS and the release of calcitonin gene-related peptide (CGRP) and N-methyl-D-aspartate receptor (NMDAR) in the dorsal root ganglia were measured by the immunofluorescence assay. Finally, Western blotting was performed to detect expression changes in the Ca/CaMKII/CREB pathway.

RESULTS

The KOR agonist U50488H could improve the values of TWL and MWT of NP the rats, inhibit inflammatory responses and relieve oxidative stress injury. Its mechanisms of action were associated with U50488H repression of Ca influx, reduction of CGRP and NMDAR releases in the dorsal root ganglia and decreases in CaMKII and CREB phosphorylations in NP rats.

CONCLUSION

The KOR agonist ameliorates NP through suppressing the activity of the Ca/CaMKII/CREB pathway.

摘要

目的

观察κ阿片受体（KOR）激动剂对神经病理性疼痛（NP）大鼠的改善作用，并探讨钙离子（Ca）/钙/钙调蛋白依赖性蛋白激酶II（CaMKII）/环磷酸腺苷反应元件结合蛋白（CREB）通路的作用机制。

方法

将40只Sprague Dawley大鼠随机分为四组：假手术组（Sham组）、NP模型组（NP组）、NP + KOR激动剂U50488H组（NU组）和NP + 特异性CaMKII拮抗剂（KN93）+ U50488H组（NKU组）。测定每组大鼠的热缩足潜伏期（TWL）和机械缩足阈值（MWT）。采用酶联免疫吸附测定法检测炎症因子和氧化应激因子的变化，并用TUNEL染色观察背根神经节的凋亡率。通过免疫荧光测定法测量背根神经节中Ca浓度、氧化应激指标ROS含量以及降钙素基因相关肽（CGRP）和N-甲基-D-天冬氨酸受体（NMDAR）的释放。最后，采用蛋白质免疫印迹法检测Ca/CaMKII/CREB通路的表达变化。

结果

KOR激动剂U50488H可改善NP大鼠的TWL和MWT值，抑制炎症反应并减轻氧化应激损伤。其作用机制与U50488H抑制Ca内流、减少背根神经节中CGRP和NMDAR的释放以及降低NP大鼠中CaMKII和CREB的磷酸化有关。

结论

KOR激动剂通过抑制Ca/CaMKII/CREB通路的活性改善NP。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d56/9140919/560be293f2b5/JIR-15-3039-g0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d56/9140919/411c8d5f25cf/JIR-15-3039-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d56/9140919/2feb6662f31f/JIR-15-3039-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d56/9140919/28898ef3c2c3/JIR-15-3039-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d56/9140919/9ad25927a85d/JIR-15-3039-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d56/9140919/884d4057144b/JIR-15-3039-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d56/9140919/f7a0189b7e59/JIR-15-3039-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d56/9140919/8b51099a1552/JIR-15-3039-g0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d56/9140919/006b057480e2/JIR-15-3039-g0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d56/9140919/560be293f2b5/JIR-15-3039-g0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d56/9140919/411c8d5f25cf/JIR-15-3039-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d56/9140919/2feb6662f31f/JIR-15-3039-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d56/9140919/28898ef3c2c3/JIR-15-3039-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d56/9140919/9ad25927a85d/JIR-15-3039-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d56/9140919/884d4057144b/JIR-15-3039-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d56/9140919/f7a0189b7e59/JIR-15-3039-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d56/9140919/8b51099a1552/JIR-15-3039-g0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d56/9140919/006b057480e2/JIR-15-3039-g0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d56/9140919/560be293f2b5/JIR-15-3039-g0009.jpg

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