青风藤和青藤碱在体外及体内对吗啡依赖模型纳洛酮催促戒断反应的影响(英文)

Effect of Caulis Sinomenii and sinomenine on naloxone-precipitated withdrawal response in morphine-dependent models in vitro and in vivo

背景:青风藤临床用于治疗阿片类戒断综合征有明显的疗效,但该药的作用及作用机制尚未明确。目的:探讨中药青风藤及其有效成分青藤碱对吗啡依赖动物模型催促戒断反应的影响。设计:完全随机对照实验研究。单位:解放军第一军医大学中医系。对象:体外实验研究对象为豚鼠离体回肠,分为正常回肠对照组,吗啡依赖回肠组,青风藤系列剂量组,青藤碱系列剂量组和尼莫地平组。体内实验研究对象为昆明种小鼠,共100只,雌雄各半,体质量18～24g,随机分为正常对照组,吗啡依赖模型组,青风藤组,青藤碱组和丁丙诺啡组。干预:体外实验,在吗啡依赖豚鼠回肠段的恒温浴槽中,预先加入青风藤醇提液(1,2,4g/L),青藤碱(10,50,150μmol/L)或尼莫地平(0.3μmol/L),1min后再用纳洛酮催促。体内实验,对吗啡依赖小鼠分别给予青风藤醇提液(20g/kg,灌胃),青藤碱(60mg/kg,腹腔注射),丁丙诺啡(0.4mg/kg,腹腔注射),或同体积生理盐水(腹腔注射),连续给药3d,药后30min给予纳洛酮催促。豚鼠离体回肠实验采用PCLAB生物信号采集系统测定豚鼠回肠收缩张力变化。吗啡依赖小鼠催促戒断试验观察纳洛酮催促后30min内各组小鼠跳跃反应的动物数及小鼠体质量的改变,连续观察4d。主要观察指标:①豚鼠回肠收缩张力。②小鼠跳跃反应的动物数。

BACKGROUND:Caulis Sinomenii has significant therapeutic effects on opioid addiction syndrome;however,its effects and mechanism remain unclear. OBJECTIVE:To investigate the effects of Caulis Sinomenii and its active component,sinomenine on withdrawal response in morphine dependent models. DESIGN:A completely randomized controlled study. SETTING:This study was carried out in the Department of Traditional Chinese Medicine,First Military Medical University of Chinese PLA. MATERIALS:The isolated guinea pig ileum segments were studied in vitro,and were randomly divided into normal control group,morphine dependent group,three dose groups of Caulis Sinomenii,three dose groups of sinomenine,and nimodipine group.One hundred Kuming mice,half male and half female,weighing 18 g to 24 g,were randomly divided into normal control group,morphine dependent model group,Caulis Sinomenii group,sinomenine group,and buprenorphine group. INTERVENTIONS:The Caulis Sinomenii(1, 2, 4 mg/mL, sinomenine(10, 50, 150 μmol/L)and nimodipine(0.3 μmol/L)were administered 1 minute before naloxone was added in thermostat water bath of morphine dependent ileum segments in vitro. Caulis Sinomenii(20 g/kg,ig),sinomenine(60 mg/kg,ip),buprenorphine(0.4 mg/kg,ip),or saline with the same volume(ip)were respectively given to morphine dependent mice 30 minutes before naloxone treatment for 3 days continuously in vivo.The changes of the contracted tension in ileum segments were measured by PCLAB biologic signal collection system.The jumping incidences of mice in each group 30 minutes after naloxone administration and the body mass of the mice were recorded, and the observation in vivo was done for 4 days. MAIN OUTCOME MEASURES:①the contracted tension in ileum segments.②the number of mice with jumping incidences.③the changes of body mass of mice. RESULTS:In test of the isolated guinea pig ileum,the naloxone precipitated contracted tensions in normal control group and morphine dependent model group were(0.46±0.167) g and(2.11±0.566) g respectively.The difference was significant(t=7.933.P< 0.01).The naloxone precipitated contracted tensions in the three dose groups of Caulis Sinomenii were(1.37±0.33) g,(0.85±0.271) g and(0.62±0.137) g,respectively,which had significant differences as compared with those of morphine dependent model group(t=3.203,5.701,7.268.P< 0.01).The naloxone precipitated contracted tensions in the three dose groups of sinomenine were(1.78±0.355) g,(1.28±0.233) g and(0.88±0.232) g respectively,among which,those in the middle dose and high dose groups had significant differences as compared with those of morphine dependent model group(t=3.843,5.694,P< 0.01).In naloxone precipitated withdrawal test of morphine dependent model in mice,on day 7,day 8,and day 9(morphine had been withdrawn),the naloxone precipitated jumping incidences of mice in morphine model group were the most,and those in Caulis Sinomenii group and in sinomenine group were less.There were significant differences among different groups as indicated by Chi square test(χ2 =42.776,37.960,22.355,P=0.000).Within the 7 days of morphine dependent model establishing,the body mass of the mice was significantly decreased.After morphine was withdrawn,the body mass of the mice was gradually restored and increased on day 9 and day 10.In comparison with morphine dependent model group,body mass restoration of mice in the Caulis Sinomenii group and sinomenine group was more rapidly.On day 10,the body mass of the mice in the buprenorphine group was decreased significantly as compared with that in the Sinomenii group and sinomenine group,which had significant difference(t=5.871,P< 0.01,t=2.819,P< 0.05). CONCLUSION:Caulis Sinomenii and sinomenine can effectively inhibit naloxone precipitated withdrawal response in morphine dependent animal models both in vivo and in vitro.