新型AMPA受体调节剂LCX001抗阿片受体激动剂TH-030418致呼吸抑制效应及其机制  

Effect of a novel AMPA receptor modulator LCX001 against respiratory depression induced by opioid receptor agonist TH-030418

作　　者：高翔[1] 樊永正 代威 雍政 苏瑞斌 GAO Xiang;FAN Yong-zheng;DAI Wei;YONG Zheng;SU Rui-bin(State Key Laboratory of Toxicology and Medical Countermeasures,Institute of Pharmacology and Toxicology,Academy of Military Medical Sciences,Beijing 100850,China;The 991th Hospital of Joint Logistic Support Force,Xiangyang 441000,China)

机构地区：[1]军事科学院军事医学研究院毒物药物研究所,抗毒药物与毒理学国家重点实验室,神经精神药理学北京市重点实验室,北京100850 [2]联勤保障部队第九九一医院,湖北襄阳441000

出　　处：《中国药理学与毒理学杂志》2022年第1期34-40,共7页Chinese Journal of Pharmacology and Toxicology

基　　金：国家科技重大专项(2015ZX09501003)。

摘　　要：目的评价新型α-氨基-3-羟基-5-甲基-4-异吃恶唑丙酸(AMPA)受体调节剂LCX001对抗阿片类药物致呼吸抑制效应,并探讨其可能的作用机制。方法 (1) SD大鼠iv给予阿片受体激动剂TH-030418 20μg·kg^(-1)建立呼吸抑制模型,15 min后,iv给予LCX001 0(模型组),5,10和20 mg·kg^(-1)(模型+LCX001治疗组),并检测大鼠肺功能参数[每分钟通气量(MV)、呼吸频率(RF)和呼吸气道阻力(EP)]。(2)大鼠iv给予阿片受体激动剂TH-030418 20μg·kg^(-1)建立呼吸抑制模型,5 min后,iv给予LCX001 0(模型组),5,10和20 mg·kg^(-1)(模型+LCX001治疗组),并检测大鼠动脉血气参数[氧分压(p O;)、二氧化碳分压(p CO;)和血氧饱和度(s O;)]变化。(3)大鼠ip给予20%羟丙基-β-环糊精作为溶剂对照组、ip给予LCX001 20 mg·kg^(-1)作为LCX001对照组、iv给予TH-030418 20μg·kg^(-1)作为模型组和ip给予LCX001 20 mg·kg^(-1)15 min后再iv给予TH-030418 20μg·kg^(-1)作为模型+LCX001预防组,并采用脑微透析法测定清醒大鼠海马脑区内谷氨酸(Glu)的含量变化。结果 (1)呼吸抑制模型组大鼠在给予TH-030418后2.5 min MV和RF显著下降(P<0.01),EP显著上升(P<0.01);与模型组相比,模型+LCX001 20 mg·kg^(-1)治疗组在给予TH-030418后22.5 min MV和RF显著升高(P<0.05),在给予TH-030418后47.5 min EP显著降低(P<0.05)。(2)模型组大鼠在给予TH-030418后5 min p O;和s O;显著下降,p CO;显著上升(P<0.01);与模型组相比,模型+LCX00120 mg·kg^(-1)治疗组在给予TH-030418后15 min p O;和s O;显著上升、p CO;显著下降(P<0.01)。(3)清醒大鼠脑微透析结果显示,模型组大鼠给予TH-030418后20 min海马神经细胞外液的Glu含量与基础值相比显著下降(P<0.05);模型+LCX001 20 mg·kg^(-1)预防组大鼠在给予TH-030418后20,60,120和160 min时间点海马神经细胞外液的Glu含量较相同时间点模型组大鼠显著提高(P<0.05,P<0.01)。结论 LCX001能有效改善TH-030418所致呼吸抑制,其效应可能与调节海马脑�OBJECTIVE To evaluate the effect of LCX001,a novelα-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA) receptor modulator,on opioid-induced respiratory depression,and to explore its possible mechanism.METHODS (1) Rats were iv given opioid receptor agonist TH-03041820μg·kg^(-1)to establish a respiratory depression model.LCX001 0 (model group),5,10 and 20 mg·kg^(-1)(model+LCX001 treatment group) were iv given 15 min later,and lung function parameters of rats[minute ventilation (MV),respiratory frequency (RF) and enhanced pause (EP)]were detected.(2) Rats were iv given opioid receptor agonist TH-030418 20μg·kg^(-1)to establish a respiratory depression model,and LCX001 0 (model group),5,10 and 20 mg·kg^(-1)was iv given 5 min later (model+LCX001 treatment group).The changes of arterial blood gas parameters[oxygen partial pressure (pO;),carbon dioxide partial pressure (pCO;) and oxygen saturation (sO;)] were detected.(3) Rats were ip given 20% hydroxypropyl-β-cyclodextrin as the solvent control group,ip given LCX001 20 mg·kg^(-1)as the LCX001 control group,iv given TH-030418 20μg·kg^(-1)as the model group and ip given LCX001 20 mg·kg^(-1),15 min later,iv given TH-030418 20μg·kg^(-1)as the model+LCX001 prevention group.The content of glutamate (Glu)in the hippocampus of awake rats was measured by brain microdialysis.RESULTS (1) In the model group,MV,RF and EP decreased significantly 2.5 min after TH-030418 injection (P<0.01).Compared with the model group,the MV and RF of rats in the model+LCX001 20 mg·kg^(-1)group at the 22.5 min time point significantly increased (P<0.05),while EP decreased significantly at 47.5 min (P<0.05).(2) In the model group,pO;and sO;decreased significantly 5 min after injection with TH-030418,while pCO;increased significantly (P<0.01).Compared with the model group,pO;and sO;of the model+LCX001group (20 mg·kg^(-1)) were significantly increased,but pCO;was significantly decreased at the 15 min time point (P<0.01).(3) The result of brain microdialysis showed that the conte

关 键 词：AMPA受体调节剂 LCX001 阿片 呼吸抑制 

分 类 号：R965[医药卫生—药理学] R974[医药卫生—药学]