石菖蒲水煎剂对吗啡依赖大鼠戒断症状的治疗作用

目的：观察石菖蒲水煎剂对吗啡依赖大鼠戒断症状的治疗作用。方法：采用连续递增皮下注射吗啡,建立吗啡依赖动物模型;给石菖蒲实验组大鼠不同剂量（2.5 g/kg、5 g/kg、7.5 g/kg）的石菖蒲水煎剂灌胃后,用纳络酮催瘾（0.5 mg/kg）,观察每组大鼠戒断反应中出现的咬牙、湿狗样抖动、扭体等六种戒断症状,评价大鼠戒断反应的强度。结果：与盐水对照组比较,石菖蒲水煎剂对吗啡依赖大鼠的戒断症状均有不同程度的抑制作用,其中以5 g/kg剂量组的作用最为突出（P〈0.01）。结论：石菖蒲水煎剂能明显抑制吗啡依赖大鼠的戒断症状。     

生物碱对动物吗啡依赖性的戒断作用

目的：探讨一种可食用植物提取物——生物碱对成瘾动物依赖性的戒断作用。方法：50只雄性小鼠，分为5组各10只，第1—7天，A组小鼠尾静脉注射生理盐水200μl／只，B、C、D组注射吗啡150pg／只，E组注射生物碱1．7μg／只，每日2次；第7天时各组冉皮下注射纳络酮0．1mg／只催瘾。第8—14天，A、B组尾静脉注射生理盐水200μl／a，C与D组分别注射生物碱1．7与0．85μg／只，E组注射吗啡150μg／只。第15天再用纳络酮催瘾，观察并比较各时间段各组小鼠症状和体重的变化。结果：第7天时，B、C、D组小鼠有强烈成瘾表现；A、E组无异常。第15天时，B、E组出现明显成瘾症状；D组成瘾症状较轻；A、C组无异常。结论：可食用植物生物碱无成瘾性，对动物及人体依赖性的戒断作用有重要参考价值。     

多次电针刺激抑制大鼠吗啡戒断症状的累加效应及长时程后效应

目的：观察电针刺激对大鼠吗啡戒断症状的抑制作用是否有累加效应和长时程后效应。方法：用递增剂量吗啡连续皮下注射10天,造成大鼠吗啡依赖模型。（1）在末次注射吗啡后12小时,将大鼠随机分成4组,分别给予4次、2次、1次100Hz电针刺激（每次30min）,或不给电刺激作为对照。在末次注射吗啡24小时,观察并记录75分钟内的自然戒断症状。（2）测试自然戒断症状后,将这4组大鼠继续饲养7天后,用纳络酮（1mg/kg,i.p.)催瘾,观察记录30分钟内的戒断症状。结果：(1)4次电针刺激组抑制吗啡戒断症状的效果显著优于对照组（P＜0．01）、1次（P＜0．01）及2次（P＜0．05）电针组。（2）多次电针刺激后一周,仍可以看出电针刺激组钠络酮诱发的戒断症状均显著少于对照组（P＜0．01）,且4次电针刺激组的效果显著优于1次组（P＜0．05）。结论：（1）4次电针刺激抑制自然戒断症状的作用优于单次,说明针效有累加作用。（2）多次（2－4次）电针刺激对戒断症状的抑制作用至少可维持一周。     

和厚朴酚与厚朴酚在缓解大鼠吗啡戒断反应中对β-内啡肽的影响

背景：现代药理证实和厚朴酚与厚朴酚具有中枢抑制作用和肌肉松弛作用，且有报道证实其可缓解动物吗啡依赖戒断症状。目的：探讨和厚朴酚与厚朴酚在缓解吗啡戒断反应中对β-内啡肽的影响：设计：随机对照实验。单位：湖北民族学院医学院药理学教研室。对象：实验于2003—04—13／29进行，取成年雄性SD大鼠100只，其中30只大鼠作为对照组随机分成生理盐水组、和厚朴酚组和厚朴酚组各10只，另外70只大鼠作为吗啡依赖组，随机分成生理盐水组，和厚朴酚5，40，80mg／kg组与厚朴酚5，40，80mg／kg组7组，各10只。方法：对照组中3个亚组分别腹腔注射生理盐水0．2mL、和厚朴酚与厚朴酚各80mg／kg。吗啡依赖组大鼠逐日增量皮下注射吗啡6d，建立急性吗啡依赖大鼠及吗啡自然戒断模型．在第6天9：00最后一次给吗啡后，10：30腹腔注射给药，生理盐水组给予生理盐水0．2mL，其他6组分别给予和厚朴酚、厚朴酚各5，40和80mg／kg。于11：00分别观察吗啡依赖组每只大鼠1h内各项自然戒断症状。主要观察指标：①各组大鼠脑脊液中β-内啡肽水平。②比较吗啡依赖组中7个亚组大鼠自然戒断症状评分。结果：①脑脊液中β-内啡肽水平：对照组中和厚朴酚与厚朴酚组显著高于生理盐水组（P〈0．01），而且和厚朴酚强于厚朴酚（P〈0．05）。吗啡依赖＋生理盐水组明显低于对照＋生理盐水组（P〈0．01）。吗啡依赖组中和厚朴酚与厚朴酚5，40．80mg／kg组均高于生理盐水组（P〈0．01），而且呈量效关系。②吗啡依赖组大鼠自然戒断症状评分：和厚朴酚与厚朴酚各剂量组湿狗样抖动、舔阴，逃避症状得分均低于生理盐水组（P〈0．05，0．01），且剂量越大效果越显著；和厚朴酚与厚朴酚40，80mg／kg组咬牙、扭体及体质量丢失显著低于生理盐水组（P〈0．01）。结论：和厚朴酚与厚朴酚可明显抑制吗啡戒断反应．且抑制效应呈量效关系，这一抑制效应与脑内β-内啡肽的增加有关。这种效应对吗啡依赖大鼠和厚朴酚与厚朴酚相当，对正常大鼠和厚朴酚强于厚朴酚。     

吗啡依赖与戒断大鼠脑组织μ阿片受体的变化

背景：内源性阿片肽-阿片受体系统的改变是阿片类药物成瘾的一个重要机制。在离体条件下，给予μ阿片受体拮抗剂或激动剂可以调节阿片受体水平。但不同的实验结果差别很大。目的：用光学放射自显影术对吗啡依赖与戒断大鼠脑组织μ阿片受体进行定位和定量研究。设计：完全随机分组实验研究。地点和对象：实验在第二军医大学长征医院麻醉科完成，对象为雄性SD大鼠30只，体质量180—220g，由第二军医大学动物实验中心提供。干预：30只SD大鼠随机分为吗啡依赖组、吗啡戒断组和生理盐水对照组，每组10只。依赖组和戒断组大鼠以腹腔注射吗啡的方法建立吗啡依赖模型，戒断组在成瘾后腹腔注射纳洛酮5mg／kg诱导戒断24h，对照组注射生理盐水。主要观察指标：大鼠不同脑区μ阿片受体特异性结合密度。结果：依赖组大鼠与对照组大鼠相比，额叶皮质、海马、纹状体、丘脑、下丘脑的μ受体特异性结合密度发生非常显著下降(t=11．54，17．82，15．80，8．35，13．78，P&;lt;0．01)，下降幅度分别为22％，49％，21％，28％，39％；戒断组大鼠与吗啡依赖组比较，额叶皮质、海马、纹状体、丘脑、下丘脑的μ受体特异性结合密度发生了显著的上调(t=3．72，7．77，5．84，3．06，11．24，P&;lt;0．01)，上调幅度分别为10％，38％，12％，13％，58％。但除下丘脑外(t=1．64，P&;gt;0．05)，其余脑区的μ受体特异性结合密度仍非常显著地低于正常水平(t=6．76，11．73，10．19，5．46，P&;lt;0．01)。结论：大鼠不同脑区在吗啡成瘾过程中μ阿片受体出现明显下调，予纳洛酮催促戒断，μ阿片受体较依赖组大鼠有显著回升，但仍显著低于正常组水平，这可能是阿片类依赖和戒断的重要神经生物学机制之一。     

肿瘤坏死因子α在吗啡依赖和戒断大鼠海马CA1区的表达变化

目的：探讨吗啡依赖和戒断大鼠海马CA1区肿瘤坏死因子α的表达变化。方法：实验于2004—04／2005—03在泸州医学院组织胚胎学实验室完成。实验动物选择普通级两三月龄雄性SD大鼠24只。按随机数字法将实验动物分为4组：对照组、吗啡依赖组和盐酸纳洛酮催促戒断1h组和戒断3h组（后两组合称戒断组），每组6只。采用剂量递增法建立吗啡依赖动物模型，用纳洛酮催促吗啡依赖动物戒断反应。具体方法为每天两次在大鼠背部皮下注射盐酸吗啡，首日10mg／kg，隔日每次增加10mg／kg，至第6天末次注射50mg／kg。吗啡依赖组末次注射后6h麻醉下灌注固定。盐酸纳洛酮催促戒断组大鼠于末次注射吗啡6h后，以盐酸纳洛酮5mg／kg皮下注射激发戒断症状，1h和3h后，同吗啡依赖组处理实验动物。对照组大鼠按照同期平行对照的原则，以相同方式注射同体积的生理盐水。记录大鼠在正常及实验状态下的活动状况。同时取大鼠海马CA1区分别作苏木精一伊红和肿瘤坏死因子α免疫组织化学，测免疫反应阳性细胞的数量和吸光度。结果：整个实验过程未出现大鼠异常死亡，吗啡注射的所有动物均成功建立吗啡依赖动物模型，全部进入结果分析。①海马形态改变：吗啡依赖和戒断大鼠海马CA1区出现结构松散、神经元萎缩和坏死等改变。②肿瘤坏死因子α蛋白表达：对照组大鼠海马CA1区肿瘤坏死因子α蛋白表达轻度阳性，吗啡依赖组和戒断组肿瘤坏死因子α阳性细胞数均增加，各组阳性细胞主要是胶质细胞和神经元。各组阳性细胞均数与对照组比较，差异均有统计学意义[（34．83&;#177;3.54），（17．50&;#177;2．88），P〈0．01]；[（38．83&;#177;4．62），（17．50&;#177;2．88），P〈0．01]；[（58．17&;#177;6．62），（17．50&;#177;2．88），P〈0．01]。而吗啡依赖组与盐酸纳洛酮催促戒断3h组差异无统计学意义[（34．83&;#177;3．54），（38．83&;#177;4．62），P〉0．05]。吗啡依赖组和戒断组肿瘤坏死因子α阳性细胞吸光度增加，各组阳性细胞吸光度均数与对照组比较差异也均有统计学意义[（0．3780&;#177;0．0094），（0．3108&;#177;0．0010），P〈0．01]；[（0.3999&;#177;0．0120）,（0．3108&;#177;0．0010），P〈0．01]；[（0．3855&;#177;0．0066），（0．3108&;#177;0．0010），P〈0．01]，吗啡依赖组与盐酸纳洛酮催促戒断3h组比较差异无统计学意义[（0．3780&;#177;0．0094），（0．3855&;#177;0．0066），P〉0．05]。盐酸纳洛酮催促戒断1h组与戒断3h组肿瘤坏死因子α阳性细胞吸光度差异有显著性[（0．3999&;#177;0．0120），（0．3855&;#177;0．0066），P〈0．05]。结论：肿瘤坏死因子α参与了吗啡依赖和戒断的病理生理过程，可能是药物依赖形成中的脑损伤初始因素之一。     

吗啡依赖及戒断对大鼠脑源性神经营养因子表达的影响

背景：阿片类药物多次用药可引起脑内有关神经部位出现形态及功能的适应性变化，这些适应性变化是导致药物渴求和戒断后复吸的重要神经生物学基础，但其确切的分子机制目前尚不清楚。目的：研究吗啡依赖形成及戒断对大鼠脑源性神经营养因子表达的影响，以期为脑源性神经营养因子参与阿片类药物依赖及戒断反应提供实验学依据。设计：以实验动物为观察对象的随机设计，对照研究。单位：一所医科大学医院的心理卫生中心。材料：实验于2004-03／2004-07在重庆医科大学药学系药理实验室完成。选择近交清洁级Sprague-Dawley)，大鼠30只，均为雄性，体质量200～250g，购自解放军第三军医大学实验动物中心。按随机数字法将其分为空白对照组、吗啡依赖组、盐酸纳洛酮处理戒断组，每组10只。方法：采用剂量递增法皮下注射吗啡建立大鼠吗啡依赖模型，然后对戒断组大鼠皮下注射2mg／kg的盐酸纳络酮激发戒断症状空白对照组大鼠按同等剂量给予生理盐水。分别对建立模型的各组大鼠进行生物学和行为学的观察。应用免疫组化和地高辛标记寡核苷酸探针原位杂交技术检测3组大鼠不同脑区脑源性神经营养因子的表达水平。主要观察指标：①各组大鼠脑内脑源性神经营养因子蛋白、脑源性神经营养因子mRNA平均光密度的比较；②各组大鼠戒断症状评定比较。结果：吗啡依赖组大鼠前额叶皮层、蓝斑、海马脑源性神经营养因子蛋白的相对含量高于对照组(P&;lt;0．05)；吗啡依赖组大鼠前额叶皮层脑源性神经营养因子mRNA的相对含量高于对照组(P&;lt;0．05)。吗啡戒断组大鼠前额叶皮层、蓝斑、海马腑源性神经营养因子蛋白及其mRNA的相对含量均高于依赖组及对照组(P&;lt;0．05)．结论：慢性给予吗啡可影响大鼠相关脑区BDNF、蛋白及其mRNA的表达，提示脑源性神经营养因子表达的改变参与吗啡依赖及戒断反应。     

脊髓蛛网膜下腔植入海藻酸钠微囊化阿片肽能细胞对吗啡依赖大鼠戒断反应的影响

目的：观察海藻酸钠-多聚赖氨酸-海藻酸钠微囊化阿片肽能细胞(alginate-polylysine-alginate microcapsule of spium peptide cell／B-1．A-PA-OPC／B-1)脊髓蛛网膜下腔移植后对吗啡依赖大鼠戒断反应的影响，证实APA-OPC／B-1对药物依赖所产生戒断症状的改善作用。方法：取成年健康雄性Wtstar大鼠35只，采用逐日多次增量注射吗啡的方法，造成吗啡依赖性模型大鼠，其中26只模型建立成功。将模型大鼠随机分为APA-OPC／B-1组(n=13)，美沙酮组(n=5)和生理盐水组(n=8)。在腹腔注射纳洛酮催瘾后，观察不同药物治疗组模型大鼠的戒断症状评分，体质量下降值，大鼠血液一氧化氮和超氧化物歧化酶(superoxide dismutase，SOD)水平变化。结果：APA-OPC／B-1组的模型大鼠体质量下降值[24h：(22．36&;#177;3．12)＆48h：(19．06&;#177;2．56)g，72h：(17．94&;#177;3．56)g,96h：(15．25&;#177;4．01)g]及第2次催瘾时戒断症状评分[(6．81&;#177;0．26)分]明显低于与生理盐水组[24h：(34．13&;#177;4.46)g，48h：(29.87&;#177;5．69)g，72h：(24．54&;#177;5．01)g，96h：(25．20&;#177;4．68)g，(7．63&;#177;0．48)分](t=-7．14- -3．54，P&;lt;0．01)。APA-OPC／B-1组的模型大鼠两次催瘾后戒断症状评分与美沙酮组比较，差异也有显著性意义(t=4．87～8．72．P&;lt;0．01)。吗啡依赖大鼠在给予美沙酮后1，48及96h时，其血液一氧化氮和SOD水平显著高于生理盐水组(P&;lt;0．01)；吗啡依赖大鼠植入APA-OPC／B-1后1，48及96h时血液中一氧化氮和SOD水平显著高于生理盐水组(P&;lt;0．05—0．01)；而吗啡依赖大鼠植入APA-OPC／B-1后1，48h及96h时血液中一氧化氮和SOD水平显著低于美沙酮组(P&;lt;0．05-0.01)。结论：APA-OPC／B-1植入脊髓蛛网膜下腔具有减轻吗啡成瘾大鼠的戒断反应的作用。     

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&;#177;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，即列照组、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、吗啡及茛菪类生物碱合并吗啡后1h的痛阈。并于末次(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。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，吗啡组小鼠的痛闯明显下降(P&;lt;0．05或P&;lt;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7d后，明显提高吗啡依赖小鼠的痛阈(P&;lt;001)，并减少跳跃次数和跳跃动物率(P&;lt;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&;lt;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。     

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。     

Role of plasma catecholamines in eliciting cardiovascular changes seen during naloxone-precipitated withdrawal in conscious, unrestrained morphine-dependent rats

Rats given morphine (8 mg/kg i.v.) followed after 2 hr by infusions of morphine (4 mg/kg i.v.) every 2 hr for 24 hr (total infusion time of 2 min for each infusion) became dependent on morphine. Injection of the opiate antagonist naloxone (5 mg/kg) precipitated a withdrawal response including an increase in mean arterial blood pressure (BP), biphasic heart rate response and an increase in plasma norepinephrine (NE) and Epinephrine (Epi). Plasma Epi was also higher after abrupt withdrawal from morphine. After removal of adrenal glands from morphine-dependent rats, naloxone injection produced no change in the BP or plasma Epi. However, naloxone injection to morphine-dependent rats treated with phentolamine to block the alpha receptor-mediated effects of circulating catecholamines led to a significant decrease in BP even though plasma Epi increased 8-fold. In morphine-dependent rats in which NE levels in sympathetic nerves have been reduced by prior exposure to 6-hydroxydopamine, naloxone produced a biphasic BP response, an initial decrease followed by an increase along with a 3-fold increase in plasma Epi. These results suggest that Epi released from the adrenal medulla of morphine-dependent rats mediates, in large part, the autonomic withdrawal responses elicited by naloxone. Naloxone injection to control and morphine-dependent rats produced similar increases in plasma NE (2-fold) indicating that the increase in plasma NE is not responsible for the withdrawal response.(ABSTRACT TRUNCATED AT 250 WORDS)     

Modification of behavioral effects of morphine, meperidine and normeperidine by naloxone and by morphine tolerance

Lever-press responding of morphine-tolerant and nontolerant squirrel monkeys was maintained under a multiple fixed-interval 5-min, fixed-interval 5-min schedule of food or electric shock presentation. Under the multiple schedule, the first response after a 5-min interval produced either food or shock depending on the prevailing stimulus. Responding maintained by either food or shock was characterized by patterns of positively accelerated responding during the 5-min interval. Morphine (0.1-1.0 mg/kg), meperidine (0.3-10.0 mg/kg) and normeperidine (1.0-17.0 mg/kg) produced dose-related decreases in rates of responding and produced small changes in the temporal pattern of responding in monkeys not tolerant to morphine. Food- and shock-maintained responding generally were affected similarly. Naloxone (0.1-3.0 mg/kg) had no effect when given alone to nontolerant monkeys. Both morphine tolerance and naloxone administration reversed the rate-decreasing effects of morphine and shifted the morphine dose-effect function to the right. Naloxone administration and morphine tolerance also reversed the rate-decreasing effects of meperidine and normeperidine, but unlike with morphine, combinations of naloxone and meperidine or normeperidine disrupted temporal patterns of responding and, at the higher doses, increased rates of responding well above control values. Drug effects in morphine-tolerant or naloxone-treated monkeys were not dependent on the event maintaining responding as comparable local rates of responding maintained by food or shock presentation were affected similarly. It was concluded that meperidine and normeperidine possess behavioral effects in common with those of morphine as well as pronounced non-morphine-like effects which are revealed by interference with the receptors upon which morphine acts.     

Differential effects of various doses of morphine and naloxone on two nociceptive test thresholds in arthritic and normal rats

In an attempt to clearly gauge the influence of the test used on opioid effects, the present study systemically compares the effects of various doses of morphine and naloxone with 2 differentially integrated tests: a suprasegmentally integrated test, the vocalization threshold to paw pressure and a spinally coordinated reflex, the paw withdrawal to pressure. In both normal and arthritic rats, clear differential effects of the drugs were observed: low doses of morphine (0.3 and 1 mg/kg i.v.) produced marked effects on the vocalization test, especially in arthritic rats, while it was less effective on the paw withdrawal test. Naloxone and morphine at extremely low doses (3-10 micrograms/kg, and 6 micrograms/kg i.v. respectively) clearly produced marked effects on the vocalization test, but failed to modify the paw withdrawal threshold in arthritic rats. By contrast, a high dose of naloxone (1 mg/kg i.v.) induced a comparable decrease in thresholds in both tests. This comparative study clearly shows the interest of using the vocalization threshold to paw pressure as a nociceptive test for evaluation of the antinociceptive effect of opioids. In addition, it provides useful information for a better understanding of the complex effects of morphine and the opioid antagonist naloxone in arthritic rats.     

Correlation between locomotor stimulation and the electrophysiological effects of low doses of morphine on substantia nigra dopamine neurons. I. Acute drug administration

Parallel experiments were done to determine whether the behavioral effects of low doses of morphine correlated with changes in the electrophysiological activity of two subpopulations of mesencephalic dopamine neurons in rats. Acute administration of morphine sulfate (0.01 or 0.20 mg/kg i.v.) produced a naloxone antagonizable increase in locomotion and a corresponding increase in the discharge rates of Type A dopamine neurons. Morphine sulfate led to a relatively long-latency (120-200 sec) loss of spontaneous discharge activity in the majority of Type B dopamine neurons and this was blocked by a high dose of naloxone (5.0 mg/kg). Naloxone (0.10 or 5.0 mg/kg i.v.), combined with morphine, led to a paradoxical behavioral suppression. These data suggest that morphine produces opposite effects on two functionally distinct subtypes of neurons in the substantia nigra pars compacta and that behavioral output may reflect an interaction between these changes in discharge activity in mesencephalic dopamine pathways.     

Analgesia produced by normal doses of opioid antagonists alone and in combination with morphine

In a recent study [30] it was reported that naloxone, at doses normally employed for opioid antagonism, produced a dose-dependent analgesia in BALB/c mice in the formalin test. We report here that another opioid antagonists, naltrexone, also produces analgesia under these conditions. Female BALB/c mice were injected subcutaneously with naltrexone (0.01-1.0 mg/kg) or saline alone and tested for analgesia using the formalin test. Naltrexone produced a statistically significant dose-dependent analgesia, with an ED50 of 0.05 mg/kg and almost total analgesia at doses of 0.1 mg/kg or greater. To determine the relationship between naloxone analgesia and better documented forms of opioid analgesia, BALB/c mice were injected with naloxone or saline following the administration of a pre-determined ED50 for morphine and tested for analgesia using the tail-flick and formalin tests. Naloxone antagonized morphine analgesia in the tail-flick test at both doses used (0.3 and 10 mg/kg). In the formalin test, however, naloxone attenuated morphine analgesia at the lower doses (0.1 and 0.3 mg/kg) and potentiated morphine analgesia at the highest dose (10 mg/kg). The implications of this finding are discussed.     

Retardiert freigesetztes Naloxon oral: Aufhebung der Obstipation durch orales Morphin ohne Beseitigung der Analgesie

Prolonged administration of morphine for the treatment of chronic pain causes constipation requiring the use of laxatives, which may result in electrolyte deficits. Morphine-induced constipation is due to the binding of the drug to opioid receptors in the gastrointestinal tract and the brain, where it mimics the actions of enkephalins. The effect on the gastrointestinal tract seems to be more intense than the central effect. The particular pharmacokinetic of naloxone makes it possible to reduce or abolish the constipation that follows oral administration of morphine without markedly interfering with the central effect of morphine, i.e. analgesia. The results obtained with oral administration to rats of morphine and naloxone in aqueous solution have already been published [17]. Oral morphine in doses of 1, 2.5 and 5 mg/kg reduce the intestinal transit time in a dose-dependent manner (Fig. 2, filled circles). Doses of 10 and 20 mg/kg are as effective as 5 mg/kg. Naloxone 10 mg/kg administered together with morphine either prevented or attenuated the constipating effect of morphine (Fig. 2, open circles). Tail-flick latency was used as an indicator of analgesia in the animal experiment; it was significantly increased 1, 2 and 3 h after oral administration of morphine 2.5 mg/kg (Fig. 3, hatched columns). When naloxone 10 mg/kg was given with the morphine, there was no significant reduction in tail-flick latency (Fig. 3, cross-hatched columns). Thus, oral administration of naloxone in aqueous solution antagonized the constipating effect of morphine without interfering with the antinociceptive effect of morphine. Experiments carried out with oral administration to rats of slow-release naloxone instead of naloxone in aqueous solution have not so far been published. Slow-release naloxone 5 mg/kg abolished the slowing of intestinal transit caused by oral morphine 2.5 mg/kg (Fig. 4, left-hand columns). The increase in transit time following morphine 5 mg/kg was deminished by simultaneous oral administration of slow-release naloxone 3 and 5 mg/kg in a dose-dependent manner (Fig. 4, right-hand columns). The increase in tail-flick latency caused by morphine 2.5 mg/kg was reduced but not abolished by simultaneous administration of naloxone 5 mg/kg (Fig. 5). Slow-release naloxone 3 or 5 mg/kg reduced the duration without interfering with the maximum of the antinociceptive effect of morphine 5 mg/kg (Fig. 6). These results show that slow-release naloxone is more effective than naloxone in aqueous solution in antagonizing the effects of morphine: after oral administration of the slow-release preparation, even the central action of morphine is reduced. Provided that the anatomical organization of the haemorrhoidal veins in the rat is similar to that in man, slow-release naloxone will be carried by the matrix, to which it is absorbed further down in the gastrointestinal tract. It may thus even reach the rectum, from where, after having been absorbed, it bypasses the liver, enters the central nervous system and reduces the antinociceptive effect of morphine. In conclusion, it can be stated that oral administration of naloxone in combination with morphine may help to prevent constipation during the treatment of chronic pain.     

Discriminative effects of morphine in the squirrel monkey.

Squirrel monkeys were trained in a two-choice discrete trial avoidance task to discriminate between intramuscular injections of saline and 3.0 mg/kg of morphine. Morphine (0.1-10 mg/kg) produced a dose-related increase in the number of trials completed on the morphine-appropriate lever. The stimulus control produced by the discriminative effects of morphine met the following criteria for classification as a specific narcotic effect: 1) morphine-like stimulus control was produced by all other narcotic analgesics tested (fentanyl, oxymorphone, levorphanol, methadone and meperidine); 2) in so doing, these drugs spanned a 900-fold potency range relative to morphine; 3) stimulus control was blocked by the specific narcotic antagonist naloxone; and 4) stereospecificity was a requirement for stimulus control--levorphanol produced stimulus control equivalent to 3.0 mg/kg of mrophine but its optical isomer dextrorphan did not. The time course of the stimulus control produced by 3.0 mg/kg of morphine showed that the animals continued to respond on the morphine-appropriate lever up to 14 hours after morphine administration. In contrast, monkeys administered 0.01 mg/kg of fentanyl responded on the morphine lever for only as lone as 1/2 hour after fentanyl administration. Naloxone, d-amphetamine and pentobarbital all failed to substitute for morphine, Thus, this study has extended previous observations of the discriminative properties of morphine in rats by demonstrating that qualitatively similar data are produced in a second species, the squirrel monkey.     

Respiratory effects of morphine in awake unrestrained rats

This report describes a systematic analysis of opiate drug effects on ventilation and its components tidal volume and frequency in intact, awake and unrestrained rats. A whole-body plethysmographic method was used to measure these parameters of respiration while animals breathed air or various concentrations of CO2 in air. Subcutaneous doses of morphine lower than 40 mg/kg exerted little or no apparent effect in rats breathing air; in rats breathing 4 to 8% of CO2 these doses of morphine also failed to depress any of the ventilatory parameters below the level of saline controls breathing air. Doses (0.16 to 160 mg/kg) of morphine blunted the frequency response to CO2 in a biphasic manner. The effects of morphine on tidal volume consisted of a slight increase at 0.16 and 0.63 mg/kg, a dose-dependent decrease at 2.5 to 40 mg/kg and a paradoxical rise at 160 mg/kg. These complex effects of morphine on tidal volume and frequency resulted in a simple sigmoid depression of minute volume. The slope of this sigmoid dose-response curve varied with the inspirate; it increased as the concentration of CO2 was higher. Naloxone antagonized the frequency depression produced by 40 mg/kg of morphine in a dose-dependent manner at doses ranging from 0.01 to 0.16 mg/kg, but frequency decreased again at 0.63 mg/kg. The effects of naloxone on the tidal volume depression consisted of a paradoxical further decrease at 0.01 mg/kg, a dose-dependent antagonism of depression at 0.04 to 0.16 mg/kg and a stimulation above the normal control level at 0.63 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)     

小剂量MK—801加强100Hz电针抑制大鼠吗啡戒断症状的作用

目的 :观察小剂量MK 80 1(dizocilpine)是否能加强 10 0Hz电针 (electroacupuncture ,EA)抑制大鼠吗啡戒断症状的作用。方法 :大鼠皮下注射递增剂量的吗啡 5天 (每天 3次 ) ,使其对吗啡形成依赖 ,最后一次注射吗啡后 1h ,分别腹腔 (i.p .,0 .0 3mg/kg)或蛛网膜下腔 (i.t.,10 0ng/ 10 μl)注射MK 80 1,注射后 15min给予 10 0HzEA。MK 80 1注射和 10 0HzEA共进行 3次 ,两次之间相隔5h。最后一次EA结束后 30mini.p .纳洛酮 (1mg/kg)催促戒断症状 ,并观察记录 5种戒断症状的表现。结果 :(1)单纯i.p .MK 80 1仅能显著降低直立症状 ;单纯 10 0HzEA能够显著降低直立和振翼样抖动 ;i.p .MK 80 1联合 10 0HzEA能显著降低跳跃、直立、振翼样抖动和体重丢失等 4种戒断症状。 (2 )单纯i.t.MK 80 1能显著降低振翼样抖动 ;i.t .MK 80 1联合EA能显著降低上述四种戒断症状。结论 :小剂量的MK 80 1可加强 10 0HzEA抑制戒断症状的作用 ;联合使用的效果优于单纯应用EA或MK 80 1。