鞘内注射ETAR拮抗药对大鼠骨癌疼痛改善情况及其对ERK通路的影响

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摘要目的观察鞘内注射内皮素A受体(ETAR)拮抗药对大鼠骨癌疼痛(BCP)改善作用及其对细胞外调节蛋白激酶(ERK)通路的影响。方法取60只大鼠均进行鞘内置管,随机分为假手术(sham)组、假手术+ETAR拮抗药(sham+BQ123)组、骨癌痛(BCP)组、骨癌痛+ETAR拮抗药(BCP+BQ123)组。BCP组、BCP+BQ123组采用股骨远端骨髓腔内接种Walker256细胞法建立BCP大鼠模型,sham组、sham+NS同法注射等量生理盐水。建模成功大鼠于建模第14 天,BCP+BQ123组和sham+BQ123组各14只,鞘内注射7 μl BQ123;BCP组13只、sham组14只鞘内注射等量生理盐水。鞘内注射前即刻、注射后0.5、1.0、1.5、2.0、2.5、3.0 h分别评估各组大鼠疼痛行为学:机械性缩足反射阈值(PWT)、自发抬足次数(NSF);末次评估疼痛行为学后,影像学评估各组骨质破坏情况;RT-qPCR、Western blot法检测脊髓组织中内皮素1(ET1)、ETAR、ERK1/2 mRNA和蛋白表达量及p-ERK1/2蛋白表达量。结果与sham组、sham+BQ123组比较,注射前BCP组、BCP+BQ123组的PWT降低和NSF增多(P<0.05),鞘内注射后T0.5~3.0 h期间,BCP组的PWT和NSF均保持不变,而BCP+BQ123组的PWT先升高后降低,NSF先减少后增多,PWT和NSF均于1.5 h达到最高和最少,3.0 h恢复至注射前水平。胫骨骨质X线片显示,sham组和sham+BQ123组胫骨骨质密度均匀、骨皮质连续无缺失;BCP组注射后14 d出现大范围骨破坏、骨皮质缺损严重;BCP+BQ123组股骨远端见较小骨破坏病灶,部分皮质缺损。与sham组、sham+BQ123组比较,BCP组、BCP+BQ123组脊髓ET1、ETAR mRNA和蛋白及p-ERK1/2蛋白相对表达量均升高,且BCP+BQ123组低于BCP组,差异有统计学意义(P<0.05)。结论 BCP疼痛反应与脊髓ET-1及ETAR有关,鞘内注射ETAR拮抗药可有效减轻BCP大鼠的疼痛反应,可能通过抑制脊髓ERK通路发挥调控作用。

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关键词 ：骨癌痛, 内皮素A受体, 疼痛, 细胞外调节蛋白激酶

Abstract：Objective To observe the extent to which intrathecal injection of endothelin A receptor (ETAR) antagonist alleviates the pain of bone cancer pain (BCP) rats and the effect on extracellular regulatory protein kinase (ERK) pathway.Methods Sixty rats were selected for intrathecal catheterization and randomly divided into the sham operation group, sham operation + ETAR antagonist (sham+BQ123) group, bone cancer pain (BCP) group, and bone cancer pain + ETAR antagonist (BCP+BQ123) group. The BCP group and BCP+BQ123 group were inoculated with Walker256 cells in the bone marrow cavity of the distal femur to establish a BCP rat model. On the 14th day of modeling, 14 rats in the BCP+BQ123 group and sham + BQ123 group were injected with 7 μl of BQ123 intrathecally while 13 rats in the BCP group and 14 rats in the sham group were injected intrathecally with the same amount of normal saline. Immediately before intrathecal injection and 0.5, 1.0, 1.5, 2.0, 2.5, and 3.0 hours after injection, the pain behavior of rats in each group was evaluated in terms of the mechanical paw withdrawal threshold (PWT) and the number of spontaneous flinches (NSF). After the last assessment of pain behavior, the severity of bone destruction in each group was assessed via imaging. The expressions of endothelin 1 (ET1), ETAR, ERK1/2 and p-ERK1/2 were detected by RT-qPCR and Western blot.Results Compared with the sham group and sham + BQ123 group, PWT decreased while NSF increased before injection in the BCP group and BCP + BQ123 group (P<0.05). At T0.5-3.0 h after intrathecal injection, the PWT and NSF of the BCP group remained unchanged, while the PWT of the BCP + BQ123 group increased before it decreased, while the NSF decreased before it increased. Both the PWT and NSF reached the maximum and minimum at 1.5 hours, and returned to the pre-injection level at 3.0 hours. Tibia bone X-ray showed that tibia bone density was uniform in the sham group and sham + BQ123 group, and there was no loss of the bone cortex. BCP group suffered extensive bone destruction and severe bone cortical defects 14 days after injection. In the BCP + BQ123 group, there were small lesions of bone destruction in the distal femur, and some cortical defects. Compared with the sham group and sham + BQ123 group, the relative expressions of ET1, ETAR mRNA and protein and p-ERK1/2 protein in the spinal cord of the BCP group and BCP + BQ123 group were increased, but were lower in the BCP + BQ123 group than in the BCP group (P<0.05).Conclusions The pain response of BCP is related to spinal cord ET-1 and ETAR. Intrathecal injection of ETAR antagonist can effectively improve the pain response of BCP rats, possibly by inhibiting the ERK pathway of the spinal cord.

Key words： bone cancer pain endothelin A receptor pain extracellular regulatory protein kinase

收稿日期: 2020-10-15

ZTFLH:

R738.1

基金资助:青海省基础研究计划项目(2018-0302-ZJC-0042)

作者简介: 何远山,本科学历,主治医师。

引用本文:

何远山, 苏宏, 伊国恩, 张敏, 徐鹏, 李泽清. 鞘内注射ETAR拮抗药对大鼠骨癌疼痛改善情况及其对ERK通路的影响[J]. 武警医学, 2021, 32(4): 285-290. HE Yuanshan, SU Hong, YI Guoen, ZHANG Min, XU Peng, LI Zeqing. Intrathecal injection of ETAR antagonist alleviates pain in rats with bone cancer pain and its effect on ERK pathway. Med. J. Chin. Peop. Armed Poli. Forc., 2021, 32(4): 285-290.

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http://journal08.magtechjournal.com/Jwk_wjyx/CN/ 或 http://journal08.magtechjournal.com/Jwk_wjyx/CN/Y2021/V32/I4/285

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