东莨菪碱对吗啡致小鼠依赖性的影响

背景莨菪碱类药物在改善微循环、抗休克和作为中药麻醉剂在我国临床上已广泛应用.但东莨菪碱抗吗啡成瘾作用的动物实验报道较少.目的了解东莨菪碱对吗啡致小鼠依赖性的影响,为开发东莨菪碱药物有无戒毒作用提供实验室依据.设计完全随机、实验对照、开放性实验研究.地点和对象河北工程学院生理实验室;实验对象为清洁级雄性昆明小鼠60只,2月龄,体质量(20±2)g,由河北医科大学实验中心动物室提供.干预将60只小鼠随机抽签分为6组,每组10只.正常对照组(盐水组),吗啡组,4mg/kg东莨菪碱组,0.4mg/kg东莨菪碱组,吗啡+4mg/kg东莨菪碱组,吗啡+0.4mg/kg东莨菪碱组.各组小鼠腹腔注射相应药物,1次/d,连续7 d.6组分别于第1～7天用热板法观察给药后1 h的痛阈.并于第7天给药后6 h,腹腔注射纳络酮5 mg/kg催促,观察30 min内小鼠跳跃次数,并结合第1,7天肛温评定小鼠依赖形成.主要观察指标各组小鼠痛阈;跳跃次数和跳跃动物数(率);肛温结果吗啡依赖组小鼠痛阈下降,跳跃次数和跳跃动物率增加,肛温下降.东莨菪碱(0.4,4 mg/kg×7 d)能明显提高依赖性小鼠的痛阈,减少跳跃次数和跳跃动物率,恢复其肛温.结论东莨菪碱有对抗吗啡致小鼠依赖性的作用.     

复方石菖蒲合剂对吗啡依赖小鼠位置偏爱效应及血中单胺类递质的影响

目的:探讨复方石菖蒲合剂对吗啡诱导的小鼠条件性位置偏爱(CPP)及血中单胺类递质水平的影响.方法:连续给予吗啡(9 mg/kg,sc)6d,引起小鼠产生显著的条件性位置偏爱效应.在训练阶段每天sc吗啡前30 min预先给予复方石菖蒲合剂组三种不同剂量的复方石菖蒲合剂(5,10和15g·kg-1)灌胃,用荧光分光光度法测定血中单胺类递质含量.同时检测对小鼠的奖赏效应或厌恶效应.结果:吗啡模型组小鼠在伴药箱中停留的时间明显延长,小鼠血中单胺类递质显著升高.复方石菖蒲合剂可显著抑制吗啡引起的小鼠位置偏爱的形成,降低血中单胺类递质水平含量.结论:吗啡诱导的小鼠位置偏爱效应与血中单胺类递质水平升高、中枢单胺类神经系统激活有关.复方石菖蒲合剂能消除吗啡诱导的小鼠条件性位置偏爱的形成,对血中单胺类递质水平的改变具有调节作用.     

东莨菪碱对吗啡致小鼠依赖性的影响

背景：莨菪碱类药物在改善微循环、抗休克和作为中药麻醉剂在我国临床上已广泛应用。但东莨菪碱抗吗啡成瘾作用的动物实验报道较少。目的：了解东莨菪碱对吗啡致小鼠依赖性的影响，为开发东莨菪碱药物有无戒毒作用提供实验室依据。设计：完全随机、实验对照、开放性实验研究。地点和对象：河北工程学院生理实验室；实验对象为清洁级雄性昆明小鼠60只，2月龄，体质量(20&;#177;2)g，由河北医科大学实验中心动物室提供。干预：将60只小鼠随机抽签分为6组，每组10只。正常对照组(盐水组)，吗啡组，4mg／kg东莨菪碱组，0．4mg／kg东莨菪碱组，吗啡+4mg／kg东莨菪碱组，吗啡+0．4mg／kg东莨菪碱组。各组小鼠腹腔注射相应药物，1次／d，连续7d。6组分别于第1～7天用热板法观察给药后1h的痛阈。并于第7天给药后6h，腹腔注射纳络酮5mg／kg催促，观察30min内小鼠跳跃次数，并结合第1，7天肛温评定小鼠依赖形成。主要观察指标：各组小鼠痛阈；跳跃次数和跳跃动物数(率)：肛温结果：吗啡依赖组小鼠痛阈下降，跳跃次数和跳跃动物率增加，肛温下降。东莨菪碱(0．4，4mg／ks&;#215;7d)能明显提高依赖性小鼠的痛阈．减少跳跃次数和跳跃动物率，恢复其肛温。结论：东莨菪碱有对抗吗啡致小鼠依赖性的作用。     

纳洛酮对吗啡依赖小鼠条件性位置偏爱及戒断症状的影响

目的：了解阿片受体拮抗剂纳洛酮在吗啡依赖及其戒断症状中的作用。 方法：实验于2003-09／12在中南大学湘雅二医院医学实验动物中心完成。①分组：Balb／C小鼠30只，随机分为生理盐水组、吗啡组、吗啡＋纳络酮组，每组10只。②干预：吗啡组：盐酸吗啡每天两次腹腔注射，起始剂量为每次10mg／kg，逐日递增，直至第7天时每次70mg／kg；吗啡＋纳洛酮组：吗啡注射方式方法同吗啡组，但在每次吗啡注射前5min。皮下注射纳洛酮1mg／kg；生理盐水组：按照同期对照的原则注射生理盐水作为阴性对照。③进入实验程序前一天及实验处理因素终止后6h测评各组小鼠条件性位置偏爱，即观察30min内小鼠在位置偏爱实验箱白侧（伴药侧）的停留时间。④于末次注射吗啡后6h观察各组小鼠30min内跳跃反应次数、戒断反应前后1h内跳跃潜伏期、直立、躯体拉伸、体质量丧失量及腹泻等症状。 结果：30只小鼠均进入结果分析。①终止处理因素后6h时，吗啡组小鼠30min内在位置偏爱实验箱白侧的停留时间为（457＋304）s，吗啡＋纳洛酮组小鼠30min内在位置偏爱实验箱白侧的停留时间为（154＋118）s，与生理盐水组（121&;#177;111）s比较，差异有显著性（P〈0．01，P〈0．05）。②吗啡注射同时给予纳洛酮干预减轻了戒断体征：在终止处理因素后6h，吗啡组和吗啡＋纳洛酮组小鼠均表现跳跃次数增加、起跳潜伏期缩短、躯体拉伸次数增加、腹泻和体质量丧失量增加，与生理盐水组比较，差异均具有显著性（P〈0．05）；吗啡组还出现直立次数增多。 结论：纳洛酮能有效对抗吗啡所致的小鼠吗啡依赖，并且能有效减轻吗啡撤药时戒断体征。     

纳洛酮对吗啡依赖小鼠条件性位置偏爱及戒断症状的影响

目的:了解阿片受体拮抗剂纳洛酮在吗啡依赖及其戒断症状中的作用。方法:实验于2003-09/12在中南大学湘雅二医院医学实验动物中心完成。①分组:Balb/C小鼠30只,随机分为生理盐水组、吗啡组、吗啡 纳络酮组,每组10只。②干预:吗啡组:盐酸吗啡每天两次腹腔注射,起始剂量为每次10mg/kg,逐日递增,直至第7天时每次70mg/kg;吗啡 纳洛酮组:吗啡注射方式方法同吗啡组,但在每次吗啡注射前5min,皮下注射纳洛酮1mg/kg;生理盐水组:按照同期对照的原则注射生理盐水作为阴性对照。③进入实验程序前一天及实验处理因素终止后6h测评各组小鼠条件性位置偏爱,即观察30min内小鼠在位置偏爱实验箱白侧(伴药侧)的停留时间。④于末次注射吗啡后6h观察各组小鼠30min内跳跃反应次数、戒断反应前后1h内跳跃潜伏期、直立、躯体拉伸、体质量丧失量及腹泻等症状。结果:30只小鼠均进入结果分析。①终止处理因素后6h时,吗啡组小鼠30min内在位置偏爱实验箱白侧的停留时间为(457±304)s,吗啡 纳洛酮组小鼠30min内在位置偏爱实验箱白侧的停留时间为穴154±118雪s,与生理盐水组穴121±111雪s比较,差异有显著性(P<0.01,P<0.05)。②吗啡注射同时给予纳洛酮干预减轻了戒断体征:在终止处理因素后6h,吗啡组和吗啡 纳洛酮组小鼠均表现跳跃次数增加、起跳潜伏期缩短、躯体拉伸次数增加、腹泻和体质量丧失量增加,与生理盐水组比较,差异均具有显著性(P<0.05);吗啡组还出现直立次数增多。结论:纳洛酮能有效对抗吗啡所致的小鼠吗啡依赖,并且能有效减轻吗啡撤药时戒断体征。     

莨菪类生物碱对吗啡依赖小鼠痛阈影响的比较

目的：观察莨菪类生物碱对吗啡依赖小鼠痛阈的影响。方法：连续腹腔注射吗啡(10mg／kg，1次／d，共7d)建立小鼠依赖模型，并腹腔注射莨菪类生物碱(4mg／kg，1次／d，共7d)。结果：吗啡组小鼠痛阈明显下降。东莨菪碱能显著提高吗啡依赖小鼠的痛阈。同剂量山莨菪碱和阿托品均有对抗吗啡依赖小鼠的痛阈下降的现象。结论：莨菪类生物碱中，东莨菪碱在提高吗啡依赖小鼠痛阈的作用最强。     

东莨菪碱对骨癌痛鼠吗啡镇痛效果的影响

目的:观察腹腔内注射毒蕈碱受体拮抗剂东莨菪碱对骨癌痛鼠吗啡镇痛效果的影响.方法:使用Walker256大鼠乳腺癌细胞建立大鼠胫骨癌痛模型.在建模2周内对建模胫骨进行X线摄片观察肿瘤性溶骨破坏的程度,将模型成功大鼠随机均分为4组(n=10).对照组(C组),每日予生理盐水(NS)1 ml腹腔注射(ip),30 min后予NS 1 ml ip;吗啡治疗组(M组),每日予NS 1 ml ip,30min后予吗啡4 mg/kg(NS稀释至1 ml)ip;东莨菪碱治疗组(S组),先给予东莨菪碱0.5 mg/kg (NS 稀释至1 ml)ip,30 min后予NS 1 ml ip;吗啡复合东莨菪碱组(MS组),先给予东莨菪碱0.5 mg/kg(NS稀释至1 ml)ip,30 min后予吗啡4 mg/kg(NS稀释至lml)ip;各组持续用药6d,给药1h后测自由行走痛行为学评分、机械痛及热痛痛阈值的变化.结果:大鼠在2周时出现自由行走痛行为学改变,机械痛阈值及辐射热痛阚值下降.治疗后,与C组和S组相比,M组和MS组自由行走痛行为学评分下降(P＜ 0.05),机械痛和热痛痛阈值升高(P＜0.05);与M组相比,MS组机械痛阚值及辐射热痛阈值升高,但无统计学意义.结论:吗啡可有效治疗骨癌痛,复合应用东莨菪碱(0.5 mg/kg)可增强吗啡镇痛效果.     

莨菪类生物碱对吗啡依赖小鼠痛阈影响的比较

目的:观察莨菪类生物碱对吗啡依赖小鼠痛阈的影响。方法:连续腹腔注射吗啡(10mg/kg,1次/d,共7d)建立小鼠依赖模型,并腹腔注射莨菪类生物碱(4mg/kg,1次/d,共7d)。结果:吗啡组小鼠痛阈明显下降。东莨菪碱能显著提高吗啡依赖小鼠的痛阈。同剂量山莨菪碱和阿托品均有对抗吗啡依赖小鼠的痛阈下降的现象。结论:莨菪类生物碱中,东莨菪碱在提高吗啡依赖小鼠痛阈的作用最强。     

吗啡耐受小鼠脊髓突触素的变化

目的：观察氯胺酮抗吗啡耐受过程中对小鼠脊髓突触素的影响。方法：实验于2003-06／09在华中科技大学同济医学院附属同济医院麻醉学实验室完成。昆明种小鼠24只，随机分为4组（n=6）：对照组。皮下注射生理盐水（10mL／kg）30min后腹腔注射生理盐水（10mL／kg）；慢性吗啡耐受模型组，皮下注射吗啡（10mg/kg）30min后腹腔注射生理盐水（10mL／kg）；氯胺酮10mg／kg组：吗啡皮下注射30min后腹腔注射氯胺酮10mg／kg，（用前稀释成10mL／kg，以与对照组等容）；氯胺酮20mg／kg组：吗啡皮下注射30min后腹腔注射氯胺酮20mg／kg。各组每天重复用药两次，连续9d，隔天最后一次给药后1h，采用测触痛阈法测撤爪反应的机械触痛阈值作为疼痛指标。采用免疫组织化学，方法测定脊髓突触素免疫反应阳性产物在吗啡耐受过程中的变化。结果：在实验过程中无动物死亡，全部进入结果分析。①对照组在各时间点撤爪阈值无明显变化；慢性吗啡耐受模型组在第1、3天撤爪阈值与对照组在同时间点撤爪阈值相近，第5天至第9天撤爪阈值进一步下降。氯胺酮10mg／kg组撤爪阈值的变化趋势与慢性吗啡耐受模型组相同；氯胺酮20mg／kg组的撤爪阈值变化不明显，在各时间点与对照组相近，表明20mg／kg氯胺酮与吗啡合用均有部分抗吗啡耐受形成的作用。②在对照组小鼠脊髓中，脊髓背角Ⅰ-Ⅱ层突触素免疫阳性产物呈棕黄色颗粒状，分布在胞浆中；慢性吗啡处理后第9天慢性吗啡耐受模型组脊髓背角Ⅰ-Ⅱ层突触素免疫阳性产物表达较对照组明显密集；氯胺酮10mg／kg组突触素免疫阳性产物表达与慢性吗啡耐受模型组相比变化不明显；氯胺酮20mg／kg组脊髓背角Ⅰ-Ⅱ层突触素免疫阳性产物表达比慢性吗啡耐受模型组相比明显稀疏，与对照组相似。③慢性吗啡耐受模型组第9天脊髓突触素阳性产物吸光度值比对照组明显增加，可达35％，差异有显著性[（97&;#177;11），（72&;#177;9），P〈0．05[；氯胺酮10mg／kg组与慢性吗啡耐受模型组脊髓突触素阳性产物吸光度值接近，差异无显著性[（93&;#177;11），（97&;#177;11），P〉0．05]，而明显高于对照组，差异有显著性（P〈0．05）；氯胺酮20mg／kg组第9天突触素阳性产物吸光度值分别比慢性吗啡耐受模型组降低20％，差异有显著性[（78&;#177;7），（97&;#177;11），P〈0．05]，而与对照组相比，差异无显著性（P〉0．05）。表明20mg／kg氯胺酮可以显著降低小鼠耐受时脊髓突触素吸光度。结论：吗啡耐受的机制可能涉及脊髓突触素的上调，氯胺酮可能通过抑制脊髓突触素上调而具有部分抗吗啡耐受作用。     

莨菪类生物碱与吗啡并用对小鼠吗啡成瘾性的影响

背景莨菪碱类药物改善微循环和作为中药麻醉剂已在国内临床上广泛应用,但莨菪类生物碱抗吗啡成瘾作用的动物实验缺乏深入报道.目的观察莨菪类生物碱与吗啡合用对抗吗啡致小鼠依赖性的作用,以期为开发防治阿片类物质成瘾的莨菪类药物提供实验学依据.设计以实验动物为研究对象的随机对照实验.单位一所大学医学院的生理学实验室.材料本实验于2004-06/2004-08在河北工程学院医学部生理学实验室完成.选择健康雄性昆明小鼠50只,2月龄,体质量(20±2)g,由河北医科大学实验动物中心提供,清洁级.方法依据吗啡成瘾动物的依赖性评价指标,选择痛阈和纳络酮跳台反应作为观察项目.将50只小鼠随机分为5组,即对照组、吗啡组、东莨菪碱组、山莨菪碱组和阿托品组,每组10只.分别于第1天至第7天每天用热板法观察腹腔注射生理盐水、吗啡及莨菪类生物碱合并吗啡后1 h的痛阈.并于末次(第7天)给药后6 h,腹腔注射纳络酮5 mg/kg催促,观察30 min内小鼠跳跃次数.主要观察指标①吗啡成瘾小鼠的痛阈;②吗啡成瘾小鼠的跳跃次数和跳跃动物数(率).结果与对照组比较,吗啡组小鼠的痛阈明显下降(P＜0.05或P＜0.01),跳跃次数和跳跃动物率明显增加.东莨菪碱与吗啡合用7 d后,明显提高吗啡依赖小鼠的痛阈(P＜0.01),并减少跳跃次数和跳跃动物率(P＜0.05);阿托品和山莨菪碱与吗啡合用在提高吗啡依赖小鼠痛阈方面作用较弱,但减少跳跃次数和跳跃动物率的作用较强(P＜0.01).结论莨菪类生物碱均具有不同程度对抗吗啡依赖性的作用,为吗啡依赖患者的戒断作用提供重要的实验学依据.     

Benefits of external qigong therapy on morphine-abstinent mice and rats

OBJECTIVE: To exclude possible psychological effects of qigong therapy in the treatment of addiction effectively, morphine-dependence models need to be established in mice and rats. METHOD: The effects of external qi on withdrawal syndrome were examined in naloxone-precipitated mice and rats in three randomized control experiments: naloxone-precipitated test in morphine-dependent mice (n = 100 in 5 groups, 20 mice each group); conditioned position preference test in morphine-abstinent mice (n = 30 for 3 groups, 10 each); and naloxone-precipitated test with paired box in morphine-dependent rats (n = 40 for 4 groups, 10 each). RESULTS: These experiments showed that morphine-dependent mice, after external qigong (EQ) therapy, had decreased incidence of jumping and lower jumping frequencies, and attenuated loss of body weight. After EQ therapy, morphine-dependent rats had reduced withdrawal scores and body weight loss was inhibited. In the conditioned place preference test, the time spent in the drug-paired box was significantly shorter for the qigong group than for the morphine group. CONCLUSION: These results suggest that qigong might have an inhibitory effect on withdrawal syndrome, and reduce the dependence potential in mice. Three different designs confirm that the impact of qigong therapy on morphine-abstinent mice and rats is reliable and substantial. Further research on the effectiveness and the mechanism of qigong therapy on addiction is warranted.     

Glycyl-glutamine, an endogenous beta-endorphin-derived peptide, inhibits morphine-induced conditioned place preference, tolerance, dependence, and withdrawal

Glycyl-glutamine (Gly-Gln; beta-endorphin(30-31)) is an endogenous dipeptide synthesized from beta-endorphin(1-31). Previous investigations have shown that Gly-Gln inhibits the cardiovascular and respiratory depression caused by morphine and beta-endorphin(1-31), but it does not interfere with opioid analgesia. In this study, we tested whether Gly-Gln administration would influence morphine-induced conditioned place preference, tolerance, dependence, or withdrawal. For place preference experiments, rats were conditioned with morphine sulfate (2.5 mg/kg i.p.) or saline on alternate days for 6 days and tested on day 7. Glycyl-glutamine (1-100 nmol i.c.v.) pretreatment inhibited acquisition of a conditioned place preference to morphine significantly. Glycyl-glutamine (100 nmol i.c.v.) also blocked expression of a pre-established morphine place preference, but it did not interfere with acquisition of a conditioned place preference to palatable food, and it did not produce place preference or aversion when given alone to morphine-naive animals. To induce antinociceptive tolerance, rats were treated with morphine (10 mg/kg i.p.) twice daily for 7 days, and morphine antinociception was evaluated with the tail-flick test. Glycyl-glutamine (100 nmol i.c.v.) pretreatment delayed the onset of morphine tolerance significantly and partially reversed pre-established tolerance. Morphine dependence and withdrawal were assessed by measuring naloxone-precipitated withdrawal symptoms. Glycyl-glutamine inhibited the development of morphine dependence when given to rats twice daily immediately before they received morphine (10 mg/kg i.p.) and suppressed withdrawal symptoms of rats with subcutaneously implanted morphine pellets when administered 5 min before withdrawal was induced with naloxone. Glycyl-glutamine thus attenuates morphine-induced conditioned place preference, tolerance, dependence, and withdrawal without compromising morphine analgesia.     

构建吗啡依赖条件性位置厌恶模型大鼠伏隔核壳区相关基因的表达

背景：腺苷酸环化酶Ⅷ涉及促进吗啡耐受、戒断和强化性能,对晚期长时程增强效应、长时程记忆和对应激的适应等可塑性变化中发挥重要的作用.目的：基于慢性吗啡依赖大鼠纳洛酮催瘾戒断建立的条件性位置厌恶动物模型,观察在条件性位置厌恶建立前后,与成瘾密切相关脑区伏隔核壳区内腺苷酸环化酶Ⅷ基因表达的适应性变化.方法：选用清洁级雄性S D大鼠,设模型组（吗啡＋纳洛酮组）、吗啡＋盐水组和盐水＋纳洛酮组.模型组采用连续6.5 d慢性吗啡腹腔注射10 mg/kg,纳洛酮一次催瘾注射0.3 mg/kg,同时与条件性位置训练箱搭配建立大鼠条件性位置厌恶模型,对照组依模型组对照注射等体积生理盐水.在条件性位置厌恶建立前后,采用免疫组织化学方法检测伏隔核壳区内腺苷酸环化酶Ⅷ基因的表达水平.结果与结论：条件性位置厌恶建立前,3组腺苷酸环化酶Ⅷ在伏隔核壳区表达水平差异无显著性意义（F=4.651,P=0.052）;条件性位置厌恶建立后,吗啡＋纳洛酮组腺苷酸环化酶Ⅷ在伏隔核壳区（F=4.874, P=0.028）内表达水平显著高于吗啡＋盐水组和盐水＋纳洛酮组.结果提示,伏隔核壳区内腺苷酸环化酶Ⅷ水平可能是调节阿片类物质戒断所致厌恶动机的关键因子之一;腺苷酸环化酶Ⅷ基因表达水平的变化可能是条件性位置厌恶建立相关的神经适应性变化的重要分子基础之一.     

吗啡延迟预处理对大鼠心肌缺血再灌注损伤细胞色素C氧化酶的影响

[目的]探讨吗啡延迟预处理对大鼠心肌缺血再灌注损伤的保护机制.[方法]40只大鼠随机分成4组：假手术组（C组）、缺血再灌注组（I/R组）、吗啡预处理组（M组）,吗啡预处理＋阿片类受体阻断剂组（N组）,每组10只.C组仅行左冠脉套线而不阻断150 min;I/R组行左冠脉阻断30 min,再灌注120 min;M组静注吗啡0.3mg/kg,24 h后处理同I/R组;N组在静注吗啡前10 min,静注阿片类受体阻断剂纳洛酮6mg/kg,其余处理同I/R组.再灌注120min后,免疫印记法测心肌细胞色素C氧化酶（cytochrome c oxidase,CcO）表达水平,同时测心梗面积.[结果]与C组相比,I/R组、M组和N组CcO表达水平均降低;与I/R组比,M组CcO表达水平增高,心肌梗死面积减少,且差异有显著性（P＜0.05）.[结论]吗啡延迟预处理对心肌缺血再灌注损伤的保护作用可能与促进心肌CcO表达有关.     

Early postnatal stress alters place conditioning to both mu- and kappa-opioid agonists

Clinical literature has established a link between early childhood incidents of neglect and trauma and adult problems with substance abuse. In rats, such early life stress has been modeled using a maternal separation (MS) paradigm in which rat pups were removed from their mothers for a few hours daily during the first two postnatal weeks. In this study, we used the MS model to investigate the effects of early postnatal stress on place conditioning to both mu- and kappa-opioid agonists in male and female Long-Evans rats. Offspring of both rearing conditions [MS or nonhandled (NH)] were conditioned using a biased procedure to saline, the mu-opioid agonist morphine (3.0, 5.6, and 10 mg/kg s.c.), or the kappa-opioid agonist spiradoline (0.3, 1.0, and 3.0 mg/kg) for 3 days, followed by a drug-free place-conditioning test 24 h later. Saline was administered in the morning, 30 min before confinement in one compartment, whereas morphine or spiradoline was administered in a similar manner 6 h later in the opposite compartment. MS offspring spent significantly more time in the morphine-paired compartment than NH offspring, indicating a greater place preference for the mu-opioid agonist. In the case of spiradoline, NH offspring spent significantly less time in the spiradoline-paired compartment, indicating a greater aversion to the kappa-opioid agonist in these animals than in MS offspring. These findings indicate that early postnatal stress can significantly alter the rewarding or aversive value of mu- and kappa-opioid agonists when measured using place conditioning.     

毁损伏隔核、腹侧苍白球对大鼠觅药行为的影响

目的探讨伏隔核和腹侧苍白球在药物强化中的作用。方法分别毁损成瘾大鼠伏隔核、腹侧苍白球,利用条件性地点偏好实验测定术前、术后成瘾大鼠对注射吗啡的偏好分,评价伏隔核和腹侧苍白球在药物强化效应的作用。结果毁损大鼠双侧伏隔核能够完全消除大鼠对注射吗啡侧的偏好,毁损腹侧苍白球明显减少成瘾大鼠的地点偏好行为。结论伏隔核和腹侧苍白球是调节强化作用的重要位置,伏隔核－腹侧苍白球通路是药物强化的共同环路。     

Benzodiazepines increase the reward effects of buprenorphine in a conditioned place preference test in the mouse

Buprenorphine (BPN) is widely used as a substitution treatment for opioid addiction. Some cases of abuse and misuse, especially associated with various benzodiazepines (BZDs), have been described, and a previous study has shown that BZDs increase the sedative effect of BPN and decrease its anxiogenic properties. To investigate the reward effect that may lead to the abusive combination of BPN and BZD, we studied the influence of different doses of three BZDs extensively used with BPN by drug addicts on conditioned place preference behavior in mice. BPN (0.3, 1, 3 mg/kg) was injected subcutaneously into male mice alone or in combination with a BZD administered intraperitoneally: dipotassium clorazepate (CRZ; 1, 4, 16 mg/kg), diazepam (DAZ; 0.5, 1, 5 mg/kg), or bromazepam (BMZ; 0.5, 1, 3 mg/kg). Amphetamine (8 mg/kg) was used as a reference drug. Reward effects of BPN alone or in combination were measured in a conditioned place preference paradigm using an unbiased procedure. Our results showed that groups treated with BPN associated with different doses of diazepam and clorazepate, but not bromazepam, spent significantly more time in the drug‐paired compartment compared to the group treated with BPN alone. Our study shows that joint consumption of diazepam and clorazepate, but not bromazepam, can increase the reward properties of BPN alone in mice. These results could help to explain the use of this type of drug combination in the drug addict population.     

伏隔核的外壳部和核心部毁损对大鼠吗啡觅药行为的影响

背景伏隔核对吗啡觅药行为的建立起着至关重要的作用,而伏隔核内不同区域在形态学、神经化学和电生理学等方面存在明显差别.目的分析伏隔核各亚区(外壳、核心)在吗啡觅药行为中的作用,研究定向毁损对大鼠成瘾行为的影响.设计随机对照实验研究.地点和对象雄性Sprague-Dawley大鼠,由解放军第四军医大学实验动物中心提供.干预大鼠通过吗啡强化形成条件性地点偏好,在反应稳定后,使用直流电对大鼠进行外壳部或核心部毁损(或空白对照).待大鼠恢复后进行吗啡复燃,并测试其地点偏好数据.主要观察指标位置偏爱箱内最大停留时间.结果在7 d内,所有外壳毁损组和空白对照组动物均重新建立起了与毁损前相同的条件性地点偏好,最大停留时间分别为(647±46)和(662±29)s,均达到术前水平.但是,伏隔核核心部毁损却导致觅药行为的明显减退,最大停留时间由术前的(650±30)s减至术后的(463±40)s,与其他两组相比差异有显著性意义(q=3.95,4.17;P＜0.05).结论在药物相关刺激条件下,伏隔核核心在吗啡觅药行为的建立方面起重要作用.     

东莨菪碱与曲马多对术中寒战影响的临床观察

目的观察东莨菪碱与曲马多对寒战后相关反应的影响。方法选择腰硬联合麻醉下发生寒战的60例病例,随机分为曲马多(T)组,东莨菪碱(S)组和生理盐水(C)组,分别给予曲马多1.0mg/kg,东莨菪碱0.01mg/kg及生理盐水,均用生理盐水稀释成5毫升后15秒缓慢静脉推注。分别记录入室时,麻醉5分钟后,寒战3分钟后,给药后1、3、5、10、20、30分钟的SBP、DBP、MAP、HR、SPO2、寒战分级、镇静分级,恶心呕吐分级及患者自身感受,并计算RPP(心肌氧耗指数=心率×收缩压)。结果 S组心率高于另外两组;三组血压无差异;寒战评分方面,T组与C组相比有显著差异(P<0.05),S组与C组相比有显著差异(P<0.05),T组与S组相比也具有显著差异(P<0.05);T组使RPP降低的程度明显高于S组;T组不良反应少于S组。结论 1mg/kg曲马多和0.01mg/kg东莨菪碱稀释成5毫升后15秒缓慢静推均可有效治疗寒战,而且前者具有起效快,疗效明显,复发率低,不良反应少,明显降低心肌氧耗的优点。     

Differential effects of morphine on the affective and the sensory component of carrageenan-induced nociception in the rat

Pain is generally considered to have a sensory and an affective component. Clinical research has suggested that morphine more potently attenuates the affective component as compared to the sensory component. Because preclinical nociception models typically focus on the sensory component of nociception, and do not assess the affective component, it is unclear whether this potency difference of morphine can also be found in preclinical models. We therefore adapted the place conditioning paradigm to investigate negative affect accompanying carrageenan-induced (0.5% intraplantar) inflammatory nociception in rats. We found that carrageenan produced clear conditioned place aversion (CPA). Morphine (0.01-10mg/kg i.p.) dose-dependently reduced carrageenan-induced CPA with a minimal effective dose (MED) of 0.03mg/kg. Since morphine has a rewarding effect by itself, morphine-induced conditioned place preference (CPP) was also investigated. Morphine induced CPP with a MED of 1mg/kg, suggesting that the rewarding effect of morphine was not responsible for reducing carrageenan-induced CPA. We also demonstrated that morphine reduced carrageenan-induced mechanical nociception as assessed in the Randall Selitto paradigm with a MED of 1mg/kg. It is concluded that the CPA model allows for an assessment of the negative affective component of carrageenan-induced nociception. Moreover, morphine was able to reduce the affective component of nociception at doses that did not affect the sensory component of nociception, and this effect was not due to its rewarding properties. The fact that this finding mirrors the clinical situation validates the use of the CPA model for assessing the affective component of nociception.