【作者】 丘宏强；

【导师】 陈崇宏； 余涓；

【作者基本信息】 福建医科大学 ， 药理学， 2005， 硕士

【摘要】 中药丹参(Salvia miltiorrhiza Bunge)在国内被广泛用于治疗心脑血管、神经衰弱失眠等疾病,具有多种药理活性,且毒性小,其功能研究成为国内外研究热点之一。本实验室早期研究发现,丹参可以一定程度抑制吗啡依赖小鼠纳洛酮催促后引起的戒断症状。目的:以药效学研究为先导,以药理研究跟踪有效成分,筛选丹参中抗吗啡身体依赖的有效成分并对有效成分作用机制作初步的探讨。方法:(1)建立小鼠吗啡身体依赖模型,筛选丹参中抗吗啡戒断的有效成分;(2)进一步观察有效成分对小鼠吗啡依赖性形成的影响和有效成分对吗啡依赖离体豚鼠回肠标本纳洛酮催促后戒断性收缩的影响;(3)有效成分对乙酰胆碱所引起离体豚鼠回肠收缩的影响;(4)在小鼠吗整体模型和离体豚鼠回肠模型上观察丹参有效成分是否潜在自身依赖性;(5)用放射免疫法测定吗啡戒断小鼠脑内CAMP 含量,用硝酸还原酶法测定吗啡戒断小鼠血浆和全脑中NO 含量。 结果:(1)丹参中脂溶性成分SmE2 能较强地抑制小鼠吗啡戒断症状;(2)80mg/kg SmE2 连续8 天,每天两次腹腔注射可以显著降低小鼠吗啡戒断后的体重下重和跳跃反应;0.05、0.25、1.25g/l SmE2 预先孵育吗啡依赖离体豚鼠回肠可剂量依赖性地减弱其纳洛酮催促后特异性戒断收缩;(3)0.05、0.25、1.25g/l SmE2孵育正常离体豚鼠回肠可以剂量依赖性地减弱其乙酰胆碱所引起的收缩;(4)每天两次,连续8 天单纯腹腔注射SmE2(80mg/kg),经纳洛酮催促,小鼠不出现明显的体重失重和跳跃反应;单纯用1.25g/l SmE2 孵育离体豚鼠回肠,经纳洛酮催促,无戒断性收缩产生;(5)长期给予SmE2(80mg/kg,ip)可一定程度抑制吗啡戒断小鼠脑内CAMP 含量升高,但无统计学意义。此剂量给药可以显著抑制吗啡戒断小鼠血浆和脑内NO 含量的升高;结论:(1)丹参脂溶性成分SmE2 为丹参中抗吗啡戒断症状的活性物质;(2)长期给予一定剂量的SmE2 可以抑制小鼠吗啡身体依赖的形成和吗啡依赖离体豚鼠回肠的戒断性收缩;(3)SmE2 自身不存在身体依赖性;(4)SmE2 减弱小鼠吗啡戒断反应症状主要是通过中枢机制,但是对于减轻体重下降部分可能通过抑更多还原

【Abstract】 The root of Salvia miltiorrhiza Bunge has been used widely in China to treatcoronary heart disease, cerebrovascular disease, neurasthenic insomnia and otherdiseases. It has many kinds of pharmacological effects with low toxicity. Therefore,the study on the function of Salvia miltiorrhiza has become one of the hottest fields inthe world. As is shown in our early studies, Salvia miltiorrhiza can attenuate thewithdrawal symptoms precipitated by naloxone in morphine-dependent mice.Objective: Screening for anti-morphine-Physical-dependence ingredient in Salviamiltiorrhiza will be carried out through activity-guided tracing methods and thepreliminary mechanism of the action will also be studied.Methods: (1) Established a morphine physical dependent model in mice, then screenfor anti-morphine-Physical-dependence ingredient in Salvia miltiorrhiza. (2) Observethe effects of the active ingredient on the formation of morphine dependence in miceand on the withdrawal contraction precipitated by naloxone in morphine-dependentisolated guinea-pig ileum. (3) Observe the effect of the active ingredient on thecontraction induced by acetylcholine in morphine-dependent isolated guinea-pig ileum.(4) Evaluate whether the active ingredient itself produces dependence (5)Concentration of cyclic adenosine monophosphate (CAMP) in brain was measuredthrough radioimmunoassay. Nitric oxide (NO) output in brain and plasma wereassessed through method of nitrate reductase.Result: (1) SmE2, the liposoluble constituents of Salvia miltiorrhiza showedinhibitory effect on morphine withdrawal mice. (2) Peritoneal injection ofSmE2(80mg/kg, administrated for 8 days, twice a day) could attenuate the weight lossand jumping in morphine withdrawal mice significantly; Incubated with SmE2(0.05、0.25、1.25g/l), it was able to reduce dose-dependently naloxone-precipiated contractionin morphine-dependent isolated guinea-pig ileum. (3) Incubated with SmE2(0.05、0.25、1.25g/l), it was able to reduce Ach-induced contraction dose-dependently inisolated guinea-pig ileum. (4) Peritoneal injection of SmE2(80mg/kg, administratedfor 8 days, twice a day) could not produce withdrawal jumping and weight losssignificantly comparing with control group; Isolated guinea-pig ileums were simplyincubated with SmE2(1.25g/l) could not produce contraction after precipitated bynaloxone. (5) SmE2 (80mg/kg, ip) could lower CAMP output in brain of morphinewithdrawal mice, but it had no statistical significance. However, it could significantlyinhibit NO output in plasma and brain of morphine withdrawal mice.Conclusion: (1) SmE2, the liposoluble constituents of Salvia miltiorrhiza is the activesubstances that can relieve morphine withdrawal symptoms. (2) At certain doses,chronic treatment with SmE2 can inhibit the formation of morphine dependence inmice. SmE2 can also inhibit the withdrawal contraction in morphine-dependentisolated guinea-pig ileum. (3) SmE2 itself does not produce the physical dependence.(4) The mechanism that SmE2 relieve the morphine withdrawal symptoms is mainlyrelated to CNS, but with respect to the attenuation of weight loss is partially throughinhibiting peripheral gastrointestinal motility. (5) The decrease of NO concentration inbrain may be one of the mechanisms that SmE2 relieves the withdrawal symptoms. (6)The result suggests that SmE2 may be potentially useful in the treatment of opiatedependence.更多还原