青风藤及青藤碱对吗啡依赖小鼠位置偏爱效应及cAMP水平的影响

目的　观察中药青风藤及其有效成分青藤碱对吗啡诱导的小鼠位置偏爱效应的影响及其与中枢cAMP水平的关系。方法　连续给予吗啡(9mg/kg ,1次/d ,sc) 5d ,引起小鼠产生显著的条件性位置偏爱效应。用两种方式给予青风藤醇提液(5 ,10g/kg ,ig)和青藤碱(60mg/kg ,ig) ,即在训练阶段每天sc吗啡前4 5min给予和在d6测定位置偏爱前4 5min仅给药一次。大脑皮层cAMP含量采用放射免疫法测定。结果　吗啡对照组小鼠在伴药箱中停留的时间明显延长,小鼠脑组织的cAMP水平亦显著升高。青风藤或青藤碱连续用药可显著抑制吗啡引起的小鼠位置偏爱的形成,对小鼠已形成的条件性位置偏爱效应也具有一定的抑制作用。并能降低脑内cAMP含量。结论　青风藤及青藤碱能消除吗啡产生的条件性位置偏爱,其作用机制与降低中枢cAMP水平有关     

青藤碱对吗啡依赖小鼠位置偏爱效应的影响

目的 :利用条件性位置偏爱实验研究中药成分青藤碱对小鼠吗啡奖赏效应的影响。方法 :实验采用有倾向性程序。吗啡 (9mg· kg-1,sc,每日 1次 ,5 d)引起小鼠显著的位置偏爱效应。在训练阶段每天 sc吗啡前3 0 min预先给予青藤碱 (1 0 ,3 0和 60 mg· kg-1,ip)可剂量依赖性地抑制吗啡引起的小鼠位置偏爱效应。结果 :提示预先给予青藤碱能消除吗啡产生的条件性位置偏爱。     

粉防己碱对小鼠吗啡位置偏爱效应的影响(英文)

利用条件性位置偏爱实验研究钙拮抗剂粉防己碱对小鼠吗啡奖赏效应的影响 .实验采用有倾向性程序 .吗啡 ( 5mg· kg-1,sc,每日 1次 ,5d)引起小鼠显著的位置偏爱效应 .在训练阶段每天 sc吗啡前 30 min预先给予粉防己碱 ( 1 0 ,2 0和 40 mg·kg-1,ip)可剂量依赖性地抑制吗啡引起的小鼠位置偏爱效应 .而粉防己碱 ( 1 0 ,2 0和 40 mg· kg-1,ip)只在测试前 30 min给药 1次 ,不影响吗啡已形成的小鼠位置偏爱 .结果说明粉防己碱能有效地抑制吗啡偏爱效应的获得 ,但不影响其表达 .     

青藤碱对小鼠吗啡的精神依赖以及cAMP水平的影响

目的　观察中药单体成分青藤碱 (sinomenine ,Sin)对吗啡诱导的小鼠精神依赖及其中枢cAMP水平的变化的影响。方法　采用有倾向性程序引起小鼠显著的位置偏爱效应 ,利用条件性位置偏爱实验观察ipSin 10、30、6 0mg·kg-1对小鼠吗啡奖赏效应的影响 ,用放射免疫法测定小鼠脑中cAMP含量。结果　Sin可剂量依赖性地缩短小鼠在吗啡伴药箱的时间 ,对吗啡慢性作用引起的小鼠脑内cAMP含量增加具有抑制作用。结论　Sin能减弱小鼠对吗啡的精神依赖 ,降低中枢cAMP水平 ,且其本身未显示精神依赖性反应。     

钩藤碱对大鼠苯丙胺条件性位置偏爱效应的影响

目的:观察钩藤碱对大鼠苯丙胺条件性位置偏爱效应的影响及钩藤碱的奖赏效应或厌恶效应.方法:连续给予苯丙胺(2 mg/kg,sc,每日1次)4 d,引起大鼠产生显著的条件性位置偏爱效应,建立苯丙胺位置偏爱模型.钩藤碱低、中、高剂量(10、20、60 mg/kg) 苯丙胺组在训练阶段第2天sc苯丙胺12 h后分别按剂量ip给予钩藤碱,氯胺酮 苯丙胺组在训练阶段第3天sc苯丙胺之前15 min给予氯胺酮(15 mg/kg,ip),均连续3 d.钩藤碱 生理盐水组连续给予钩藤碱(60 mg/kg,ip,每日1次)4 d.结果:钩藤碱各剂量组和阳性药氯胺酮组大鼠在伴药箱的逗留时间均明显缩短,钩藤碱三剂量组随剂量的增加其作用相应增强.钩藤碱 生理盐水组大鼠不形成条件性位置偏爱.结论:预先给予钩藤碱能在一定程度上消除苯丙胺诱导的条件性位置偏爱效应,而钩藤碱本身未显示精神依赖性潜力.     

青藤碱的身体依赖性和精神依赖性实验研究

目的:观察青藤碱是否具有身体依赖性及精神依赖性,评价其安全性.方法:采用大、小鼠催促戒断模型、大鼠自然戒断模型及小鼠条件性位置偏爱模型检测青藤碱的药物依赖性.结果:在催促戒断试验中,受试的大、小鼠连续注射青藤碱10天后经纳洛酮催促,均未出现戒断症状及体重下降现象.在大鼠自然戒断试验中,青藤碱低(总给药剂量为1.05 g·kg1)、高(总给药剂量为2.1 g·kg1)两个剂量连续使用28天,停药后大鼠没有出现戒断反应及体重下降现象.在小鼠条件性位置偏爱试验中,青藤碱低、中、高三个剂量组分别连续用药6天后,小鼠在伴药盒的逗留时间均无明显延长,不形成条件性位置偏爱.结论:青藤碱不具有身体依赖性及精神依赖性,无成瘾性,使用该药安全性大.     

酸枣仁提取物对小鼠吗啡条件性位置偏爱的影响

目的:观察酸枣仁提取物对吗啡(MOR)诱导建立小鼠条件性位置偏爱(CPP)行为的影响。方法:连续给予吗啡(6mg·kg-1,sc)5d,引起小鼠产生显著的CPP效应,观察酸枣仁提取物对CPP效应的影响。结果:吗啡可诱导小鼠对伴药箱产生显著的位置偏爱;训练阶段于每次给予吗啡前30min给予酸枣仁醇提物800mg·kg-1可拮抗小鼠对吗啡产生的CPP效应(与吗啡对照组比较P<0.05),但酸枣仁醇提物200和400mg·kg-1不影响其效应(P>0.05);酸枣仁乙酸乙酯提取物13mg·kg-1、20mg·kg-1,正丁醇提取物160mg·kg-1可拮抗小鼠对吗啡产生的CPP效应(P<0.05),但酸枣仁石油醚提取物、乙醚提取物、水提物均不影响其效应(P>0.05)。结论:酸枣仁醇提物及其乙酸乙酯提取物、正丁醇提取物能在一定程度上抑制吗啡诱导小鼠建立的CPP行为。     

奥丹西隆对小鼠吗啡条件性位置偏爱效应的影响

目的 :探讨 5 -HT3 型受体特异性拮抗剂奥丹西隆对吗啡诱导的条件性位置偏爱 (CPP)效应的影响。方法 :建立小鼠吗啡CPP模型 ,观察奥丹西隆对CPP的影响。结果 :吗啡 (5mg·kg-1,sc)可诱导小鼠对伴药箱产生显著的CPP ;测试前 30min注射奥丹西隆 (0 0 1- 1mg·kg-1,sc)不影响小鼠已形成的对吗啡的位置偏爱 ;而训练阶段于每次注射吗啡同时注射奥丹西隆 (0 0 1- 0 1mg·kg-1,ip)可拮抗小鼠对吗啡的CPP效应 ,但较大剂量奥丹西隆 (1mg·kg-1,ip)则不影响其效应 ,而且此剂量单独给药亦表现出自身的CPP潜力。结论 :一定剂量的奥丹西隆可拮抗小鼠对吗啡的偏爱效应的获得 ,但不影响其表达 ,提示该类药物有治疗阿片类依赖的潜力。     

盐酸替利定的依赖性评价

目的:评价阿片类镇痛药盐酸替利定的身体依赖性和精神依赖性潜力。方法:采用小鼠、大鼠催促戒断试验、大鼠自然戒断试验、大鼠条件性位置偏爱试验和大鼠药物辨别试验对盐酸替利定进行评价,并与吗啡进行比较。结果:在小鼠、大鼠催促戒断试验中,ig替利定后有不同程度的催促戒断反应。长期给予大剂量的替利定(30d),大鼠体重明显下降(P<0·01)。在大鼠条件性位置偏爱试验中,替利定表现有明显的强化效应。在大鼠药物辨别试验中,吗啡和替利定(ig)可分别替代2·5mg·kg-1吗啡(sc)的辨别效应,其完全替代的ED50值为8·4mg·kg-1和5·6mg·kg-1。结论:盐酸替利定具有产生身体依赖性和精神依赖性的潜力,但其产生身体依赖性的潜力比等剂量的吗啡小。     

黄芪总皂苷对小鼠吗啡条件性位置偏爱及NO水平的影响

目的：观察黄芪总皂苷对吗啡诱导的小鼠条件性位置偏爱（CPP）效应的影响及其与中枢NO水平的关系。方法：建立小鼠吗啡CPP模型，观察黄芪总皂苷对CPP的影响，采用硝酸还原酶法检测小鼠脑中NO含量。结果：吗啡（6mg／kg，SC）可诱导小鼠对伴药箱产生显的CPP（P〈0．01），小鼠脑组织NO水平亦显升高（P〈0．01）；训练阶段于每次给予吗啡前30min给予黄芪总皂苷（40～160mg／kg）可拮抗小鼠对吗啡的CPP效应的（P〈0．05，P〈0．01，P〈0．01），并能降低脑内NO含量（P〈0．05，P〈0．01，P〈0．01）；仅在测试前30min一次给予黄芪总皂苷160mg／kg可抑制小鼠已形成的CPP（P〈0．01），并降低脑内NO含量（P〈0．05），而黄芪总皂苷40和80mg／kg组则不影响其效应（P〉0．05）。结论：黄芪总皂苷可抑制吗啡诱导的小鼠CPP效应的形成和表达，其作用机制可能与降低中枢NO水平有关。     

虎门合剂对吗啡诱导的大鼠条件性位置偏爱效应及伏核内BDNF蛋白表达的影响

目的:研究虎门合剂对吗啡诱导的大鼠条件性位置偏爱(CPP)效应及伏核内BDNF表达水平的调节作用。方法:使用盐酸吗啡建立大鼠CPP模型,采用Obersiver5.0行为学软件分析大鼠的CPP效应:使用高中低剂量虎门合剂干预CPP形成;利用Western blot方法测定伏核内BDNF的蛋白含量。结果:吗啡模型组大鼠在伴药箱中停留的时间较正常对照组明显延长(P<0.001),同时伏核中的BDNF蛋白表达水平亦显著升高(P<0.001)。而虎门合剂中高剂量干预组大鼠较吗啡模型组在伴药箱中停留的时间和伏核内BDNF含量则显著下降(P<0.01)。结论:中高剂量虎门合剂能显著抑制吗啡诱导的CPP效应,其作用机制与降低伏核内BDNF蛋白表达水平有关。     

Effects of test conditions on the outcome of place conditioning with morphine and naltrexone in mice

 Drug administration during test trials can increase the expression of place conditioning, offering an opportunity to determine the specificity of this enhanced response. Prior to training, Swiss-Webster mice spent similar durations in each of the distinctive compartments of a two-compartment box during three 900-s tests. During a 4-day conditioning period, daily injections of morphine (5–20 mg/kg, SC) or vehicle were differentially paired with one of two compartments of the box using an unbiased place conditioning procedure. Post-conditioning tests were conducted 2 and 3 days after the last conditioning day. Mice pre-treated during post-conditioning tests with vehicle did not show significant preference for the morphine-paired compartment when conditioned with morphine. Pretreatment with morphine (2.5–30 mg/kg, SC) led to a dose-dependent increase in time spent in the morphine-paired compartment. Post-conditioning tests in other groups of mice were conducted with heroin (0.1–3 mg/kg), fentanyl (0.01–0.3 mg/kg), cocaine (10–30 mg/kg) and pentobarbital (10–30 mg/kg), and results suggested that none of the tested drugs facilitated the expression of the morphine-conditioned place preference. In another experiment, naltrexone (0.1–10 mg/kg, SC) was administered as the conditioning drug. When tested with naltrexone (0.1–10 mg/kg), there was a dose-dependent avoidance of the naltrexone-paired compartment. Overall, the present data indicated that: (1) failure to exhibit place preference or place aversion when tested in a drug-free state does not imply the failure of conditioning procedure; and (2) effects of the morphine cue reinstatement during the post-conditioning tests appeared to be related to the unique pharmacological profile of the morphine stimulus. Received: 28 November 1997 / Final version: 23 July 1998     

青风藤对吗啡成瘾小鼠学习与记忆能力的影响

目的：研究青风藤对吗啡成瘾小鼠学习与记忆能力的影响及可能机制。方法：通过Y-迷宫观察青风藤对吗啡成瘾小鼠学习与记忆能力的影响,观察海马形态研究青风藤对海马CA1区神经元的影响。结果：青风藤治疗组与吗啡戒断组小鼠的分辨学习及记忆保持能力有显著差异．小鼠海马CA1区神经元细胞数差异显著。结论：青风藤对吗啡戒断小鼠的分辨学习及记忆保持能力有极大提高．对吗啡戒断致小鼠海马CA1区神经元的损伤有一定的治疗作用。     

The mechanisms of morphine dependence and it's withdrawal syndrome: study in mutant mice

To investigate the involvement of catecholamines and/or the cyclic AMP (cAMP) systems in the development of drug dependence, we examined whether morphine dependence was developed in tyrosine hydroxylase (TH) heterozygous (TH+/-) and cAMP response element binding protein (CREB) binding protein (CBP) heterozygous (CBP+/-) mice. Morphine (10 mg/kg) induced place preference in the wild-type mice. In the TH+/- and CBP+/- mice, however, we could not find any morphine-induced place preference. When the wild-type mice pretreated with morphine (10 mg/kg) twice a day for 5 days were challenged with naloxone (5 mg/kg), they showed increased numbers of jumping, rearing and forepaw tremor as a sign of withdrawal symptom and increased level of cAMP in the thalamus/hypothalamus, but not in the striatum. However, increased numbers of jumping and forepaw tremor in the TH+/- and CBP+/- mice and increased level of cAMP in the thalamus/hypothalamus of TH+/- mice were not observed. These results suggest that catecholamines and CBP are involved in the development of morphine dependence, and that some changes in the catecholaminergic and/or cAMP system induced by repeated morphine treatment play an important role in the addiction of morphine.     

不同产地青风藤中青藤碱的含量比较

目的比较不同产地青风藤的青藤碱含量。方法采用高效液相色谱法测定青风藤饮片中青藤碱含量。色谱柱为Lichrospher C18柱（150 mm×4.6 mm,5μm）,流动相为甲醇-水-乙二胺（40∶60∶0.2）,检测波长为262 nm,流速1.0 mL/min。结果青藤碱进样量在1～10μg范围内与峰面积呈良好的线性关系（r=0.999 8）,平均回收率为99.56%,RSD为0.81%（n=6）;江苏（三批）、湖南、湖北产青风藤药材的青藤碱含量分别为0.83%,1.11%,1.02%,1.90%,0.58%。结论不同产地青风藤药材的青藤碱含量差异显著。     

Quantification of sinomenine in caulis sinomenii collected from different growing regions and wholesale herbal markets by a modified HPLC method

Caulis Sinomenii is the dried plant stems of Sinomenium acutum and Sinomenium acutum var. cinereum and has been used in Chinese medicine for treating rheumatic diseases for over a thousand years. Previous studies have demonstrated that sinomenine is a major active constituent in both plants and can be utilized as an indicator of quality of the medicinal herb Caulis Sinomenii. Currently, S. acutum and S. acutum var. cinereum are growing over a wide geographical range in China, with equally wide variations in growing conditions. The objectives of this research were to determine whether there were difference between the species and varieties, and whether the different growing conditions could result in different quality by determining the content of sinomenine in different samples. A modified HPLC method using a diode array detector (DAD) has been developed for efficiently quantifying sinomenine in the plants. Using this method, fourteen samples of S. acutum var. cinereum and eleven samples of S. acutum from growing regions as well as eighteen herbal samples of Caulis Sinomenii from wholesale herbal markets were evaluated. The results showed that there was no marked difference in the content of sinomenine between the species and varieties collected from growing regions; however, a very large variation was found among the samples collected from different regions. Moreover, the content of sinomenine in the plants of large size (stem diameter>3 cm) was much higher than those of small size (stem diameter<1 cm). This implies that the growing region has greater impact on the quality of Caulis Sinomenii in terms of the content of sinomenine than the species and varieties. The results also showed that the content of sinomenine in commercial Caulis Sinomenii was markedly lower than that in the plants collected directly from growing regions. This suggests that to obtain the herb with higher content of sinomenine and thus ensure greater efficacy, both in clinical applications and in pharmacological investigations, the plant of Caulis Sinomenii with controlled stem size collected directly from growing regions is preferable.     

The attenuation of morphine-conditioned place preference following chronic mild stress is reversed by a CCKB receptor antagonist

Chronic exposure to mild unpredictable stress has been found to abolish the acquisition of preference for a distinctive environment paired with morphine, whereas morphine induced conditioning place preference in non-stressed rats. Chronic treatment for 21 days with the tricyclic antidepressant imipramine reversed the motivational effects produced by chronic mild stress, and animals showed a place preference for the morphine-paired compartment. When the CCK_B receptor antagonist PD-134,308 was co-administered with morphine in stressed animals during the conditioning period, the preference for the morphine-paired compartment was also re-established. The CCK_B receptor antagonist given alone did not induce rewarding effects in this paradigm. These findings indicate that the administration of a CCK_B receptor antagonist reversed the effects of chronic mild stress on opiate rewarding properties. Received: 5 October 1996/Final version: 4 December 1996     

The NMDA receptor antagonist dizocilpine (MK-801) stereoselectively inhibits morphine-induced place preference conditioning in mice

The effect of the non-competitive NMDA receptor antagonist dizocilpine (MK-801) on conditioned place preference induced by morphine was studied in mice. As expected, morphine (1–8 mg/kg, IP) elicited a significant preference for the drug-paired compartment. Pretreatment of mice with (+)-dizocilpine (0.1 and 0.2 mg/kg, IP), the more active dizocilpine enantiomer, dose-dependently reversed the conditioned place preference produced by morphine (4 mg/kg, IP), whereas (–)-dizocilpine (0.2 mg/kg, IP) did not modify morphine-induced effects. In contrast, both enantiomers of dizocilpine (at a dose of 0.2 mg/kg, IP) elicited a conditioned place preference. These data suggest that (1) NMDA receptors play a role in morphine-induced place preference, and (2) dizocilpine-reinforcing properties in the place preference paradigm do not seem to be dependent on NMDA receptor blockade.     

Single-trial conditioned place preference using intravenous morphine

Experiments were performed to investigate single-trial conditioned place preference (CPP) using intravenous morphine in rats. Single-trial CPP was obtained when morphine (8 mg/kg) was paired for either 15 or 30 min with a distinct white compartment. When morphine administration was delayed for either 15 or 25 min after the beginning of a 30-min exposure to the white compartment, single-trial CPP was not obtained. Intravenous naloxone (2 mg/kg) also blocked single-trial CPP when administered 15 min after the beginning of the 30-min exposure to the white compartment with morphine, but naloxone by itself did not alter place preference. The results from these experiments indicate that single-trial CPP using intravenous morphine may offer a useful animal model to assess the reinforcing efficacy of the initial drug experience.