中药思的明对吗啡依赖大鼠血清和尿中吗啡含量的影响

目的:考察思的明(SDM)对吗啡依赖大鼠体内吗啡代谢的影响.方法:将大鼠随机分为吗啡依赖大鼠SDM治疗组(剂量以生药材计为8 g·kg-1·d-1)、吗啡依赖大鼠非治疗组、吗啡依赖大鼠吗啡维持组、正常大鼠SDM对照组(剂量以生药材计为8 g·kg-1·d-1)和正常大鼠生理氯化钠溶液(NS)对照组.前3组以剂量递增法连续皮下注射(s.c.)吗啡7 d,建立吗啡依赖大鼠模型,d 6开始各组分别给予相应的药物.后2组从d 1开始分别灌胃(ig)给予SDM和NS.以上各组分别于d 8～d 11采集血样,d 8～d 13采集尿样.用乙酸乙酯提取血清及尿样中的吗啡,应用反相HPLC-UV法测定其浓度,并计算24 h尿液中吗啡的排泄量.结果:与非治疗组比较,SDM治疗组吗啡依赖大鼠d 8和d 9血清吗啡含量明显增高,而d 10和d 11有一定程度降低;d 8～d 10吗啡排泄量明显增高,而d 11～d 13明显降低.吗啡维持组大鼠血清中吗啡含量均明显高于各组.NS对照组和SDM对照组大鼠血清中未检测到吗啡.结论:SDM能加快体内吗啡代谢和排出的速度,这可能是SDM有脱毒和促进机体康复功效的机制之一.     

脱瘾扶正康对吗啡依赖大小鼠戒断症状的治疗作用

目的：观察及评价中药制剂脱瘾扶正康对吗啡依赖大小鼠戒断症状的治疗作用。方法：以剂量递增法形成吗啡依赖大小鼠模型,ｉｐ纳洛酮进行催促或自然戒断后,记录成瘾动物的戒断症状及体重变化,所得数据经统计学处理后进行评价。结果：脱瘾扶正康低、中、高三个剂量组均可明显降低成瘾大鼠纳洛酮催促戒断及自然戒断泊总分值,减少成瘾小鼠的跳跃反应次数,对吗啡依赖大、小鼠的体重下降有不同程度的缓解作用。脱瘾扶正康对吗啡依赖大     

清风胶囊对吗啡依赖大鼠戒断症状治疗作用的研究

目的：本实验通过制作吗啡依赖的大鼠催促戒断、自然戒断的动物模型,观察清风胶囊对吗啡依赖大鼠催促戒断、自然戒断症状的治疗作用。方法：通过复制吗啡依赖大鼠催促戒断和自然戒断模型,评价中药制剂清风胶囊对动物吗啡戒断症状的抑制作用,并与阳性药可乐定进行比较。结果：在大鼠催促戒断模型上,清风胶囊三个剂量组（0．5,1．0,2．0g／kg）ig给药均能部分控制戒断症状,并能有效抑制大鼠的体重下降。在吗啡依赖大鼠自然戒断模型上,清风胶囊中、高两个剂量组（1．0,2．0g／kg）控制体重下降作用均优于可乐定。清风胶囊中、高剂量组能明显控制吗啡依赖大鼠的自然戒断症状,与模型组比较有显著性差异（P〈0．05）。结论：清风胶囊对吗啡依赖大鼠戒断症状有肯定的脱毒治疗效果。     

金甲王颗粒对吗啡依赖猴和大鼠戒断症状的抑制作用

目的 :观察中药金甲王颗粒对吗啡依赖猴和大鼠戒断症状的抑制作用。方法 :采用吗啡依赖大鼠纳洛酮催促戒断、自然戒断模型以及吗啡依赖猴模型 ,观察金甲王颗粒对戒断症状的抑制作用。结果 :(1) 3个剂量的金甲王颗粒 (3 5 4、7 0 3和 14 0 7g生药·kg- 1 )均可显著降低吗啡依赖大鼠的催促戒断症状分值 (P <0 0 1) ;(2 )金甲王颗粒治疗组在大鼠自然戒断后期的体重恢复优于吗啡依赖组 ,3 5 4g生药·kg- 1 剂量的金甲王颗粒组大鼠体重下降百分率低于吗啡依赖组 ,但无统计学意义 (P >0 0 5 ) ;(3)在猴自然戒断治疗实验中 ,金甲王颗粒 3个剂量 (3 2 4、6 4 7、12 94g生药·kg- 1 )均能明显抑制吗啡依赖性猴的戒断症状 (P <0 0 5 ,P <0 0 1) ,金甲王颗粒中、大剂量组可明显抑制猴戒断后的体重下降 (P <0 0 5 ) ,但对体温下降的抑制作用不明显 (P >0 0 5 )。结论 :金甲王颗粒能改善吗啡依赖性动物催促戒断和自然戒断后所产生的戒断症状。     

治疗吗啡依赖和戒断的有效药物

除了阿片受体系统以外，神经递质去甲肾上腺素、多巴胺、乙酰胆碱、兴奋性氨基酸以及它们偶联的受体信息传导系统，还有５－羟色胺，γ－氨基丁酸以及大脑内具有抗阿片肽作用的多肽包括胆囊收缩素、胰高血糖素、血管紧张素Ⅱ、生长抑素和催产素，或多或少地参与了吗啡依赖...     

达尔康对吗啡依赖大鼠戒断症状的影响

目的 :观察中药达尔康对吗啡依赖大鼠戒断症状的抑制作用。方法 :采用剂量递增法皮下注射吗啡 14d和3 0d ,分别建立大鼠吗啡依赖模型 ,观察达尔康大、中、小 3个剂量对吗啡依赖大鼠纳洛酮催促和自然戒断的戒断症状及体重的影响。结果 :达尔康能显著减轻吗啡依赖大鼠ip纳洛酮引起的催促戒断症状 (P <0 .0 5 )和体重下降(P <0 .0 1) ,能抑制自然戒断大鼠体重下降 (P <0 .0 1和P <0 .0 5 )。结论 :达尔康对吗啡依赖大鼠戒断反应有明显的抑制作用     

正寿王系列药物对抗吗啡依赖动物戒断症状的实验观察

目的·· :通过动物实验 ,观察正寿王1号及2号对吗啡依赖动物模型戒断症状的影响。方法·· :皮下注射吗啡 ,建立小鼠、大鼠及犬的依赖模型 ,每种动物分成正常对照组、吗啡依赖模型组、生理盐水模拟治疗组及药物治疗组 ,观察正寿王对7种指标的影响。结果·· :正寿王主要作用为 :明显减少吗啡依赖小鼠的跳跃鼠次 (1号 :P<0.01 ,2号 :P<0.001)及其它戒断症状;减少大鼠摇头次数 (P<0.01)和攻击行为 (P<0.01),对大鼠及犬体重影响不明显;此外能明显改善犬的戒断症状。结论·· :正寿王具有控制吗啡戒断症状的效能。     

卡马西平对吗啡依赖大鼠戒断症状及ACTH的影响

目的 :观察卡马西平 (Carb)对吗啡依赖大鼠纳洛酮催促戒断症状的抑制作用及血清促肾上腺皮质激素(ACTH)水平的影响。方法 :剂量递增法皮下注射 (sc)盐酸吗啡 (Mor) ,建立大鼠吗啡依赖模型 ,腹腔注射 (ip)盐酸纳洛酮 1mg·kg- 1 催促 ,观察戒断反应并评分 ;免疫发光法测定血清ACTH水平。结果 :Carb 10 0mg·kg- 1 及 2 0 0mg·kg- 1 均可明显减轻大鼠戒断症状 (P <0 0 5 )。 10 0mg·kg- 1 剂量组的ACTH水平接近正常 ,低于Carb 2 0 0mg·kg- 1 组(P <0 0 5 )。结论 :适当剂量的卡马西平可有效控制吗啡依赖大鼠的戒断症状     

谷氨酸对吗啡依赖大鼠戒断症状的影响及其作用机制

目的:探讨谷氨酸(Glu)对吗啡依赖大鼠戒断症状的影响及其作用机制。方法:建立大鼠吗啡依赖及戒断模型并给予评分,研究Glu对吗啡依赖大鼠戒断症状的影响;通过电生理,原位杂交,免疫组化方法研究丘脑束旁核神经元动作电位变化和c-fos基因表达的变化。结果:Glu剂量依赖性增加大鼠戒断症状的总评分(P<0.05);Glu使吗啡依赖大鼠丘脑束旁核的神经元自发放电和诱发放电频率增加(P<0.05),而诱发放电抑制时程缩短(P<0.05);在Glu诱发吗啡戒断过程中,c-fos基因表达水平显著增高(P<0.01,P<0.01)。结论:Glu可通过增加细胞电脉冲的形式兴奋神经元,提高依赖状态下神经元的兴奋性,加重吗啡依赖大鼠的戒断症状;Glu也可通过c-fos间接影响Glu受体和其他的神经递质的表达起作用。     

吗啡依赖动物戒断后的焦虑情绪变化

本文采用高架十字迷宫模型和Ｖｏｇｅｌ‘ｓ饮水冲突模型观察吗啡依赖动物自然戒断后１８，２４，４８，７２，９６，１２０ｈ的焦虑情绪，结果表明吗啡依赖动物自然戒断后４８ｈ时的焦虑症状在两种模型上都最为明显，丁螺环酮可明显缓解吗啡所致的焦虑情绪，提示高架十字迷宫模型和Ｖｏｇｅｌ’ｓ饮水冲突模型可较为客观和标准地反映吗啡所致焦虑情绪。     

定志丹对吗啡依赖大、小鼠戒断症状的控制作用

目的 :观察及评价中药制剂定志丹对吗啡依赖小鼠、大鼠催促戒断症状的控制作用。方法 :按文献采用剂量递增法建立吗啡依赖小鼠、大鼠模型。末次注射吗啡后 ,给大、小鼠ig不同剂量的定志丹 ,给药后大、小鼠分别在4 0min和 30minip纳洛酮进行催促戒断 ,记录戒断症状及体重变化。实验设立了生理盐水和可乐定对照组 ;大鼠还设立了吗啡组。结果 :定志丹 10 - 2 0g·kg- 1 能显著减少吗啡依赖小鼠经纳洛酮催促出现的跳跃反应的次数 ,抑制率 39.6 % - 6 7.9% ,跳跃反应后空白对照组小鼠的体重明显减轻 (P <0 .0 1) ,而定志丹各剂量组试验前后的体重均无显著性差异 ,(P >0 .0 5 )。与空白对照组比较 ,定志丹 10 - 2 0g·kg- 1 使吗啡依赖大鼠的催促戒断症状分值明显降低 (P <0 .0 5 ) ,定志丹 2 0g·kg- 1 使各种症状发生的总次数减少 35 .3%。与空白对照组比较 ,阳性对照药可乐定组的跳跃反应潜伏时间明显延长 (P <0 .0 5 ) ;而定志丹各剂量组的跳跃反应潜伏时间虽有一定延长 ,但无统计学意义(P >0 .0 5 )。结论 :定志丹对吗啡依赖小鼠、大鼠催促戒断症状有明显的抑制作用 ,对吗啡依赖动物的体重下降有显著的缓解作用     

Antagonist-precipitated and discontinuation-induced withdrawal in morphine-dependent rhesus monkeys

Rationale  Upon discontinuation of chronic opioid treatment, withdrawal typically peaks in 1–3 days and decreases markedly within 1 week; however, persistent physiological changes have been reported long after other signs have waned. Objective  The goal of this study was to compare the discriminative stimulus, directly observable signs, and physiological effects of withdrawal in morphine-treated monkeys. Materials and methods  Monkeys received 5.6 mg/kg/12 h morphine and discriminated 0.0178 mg/kg naltrexone while responding under a fixed-ratio 5 schedule of stimulus–shock termination. Drug discrimination, behavioral observation, and telemetry were used to monitor the emergence of withdrawal, as well as any persistent changes, following discontinuation of morphine treatment. Results  Naltrexone dose (0.001–0.032 mg/kg, s.c.) was positively related with indices of withdrawal. In the discrimination study, monkeys responded on the naltrexone lever 1–5 days following discontinuation of treatment; thereafter, they responded exclusively on the saline lever. After discontinuation of morphine, the frequency of observable signs peaked within 2–3 days and most were not significantly increased after 5 days. In contrast, increased heart rate and body temperature persisted for 14 days, returning to values obtained prior to discontinuation by 21 days. Conclusions  To the extent that discriminative stimulus effects of withdrawal in nonhumans are predictive of subjective reports of withdrawal in humans, these data indicate that effective treatments for opioid dependence must address not only the short-term subjective components of withdrawal but also, and perhaps more importantly, lingering behavioral and physiological effects that might contribute to relapse long after chronic drug use is discontinued. This project was supported by USPHS Grants DA05018 and DA17918 from the National Institute on Drug Abuse. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse or the National Institutes of Health.     

Caffeine elicited withdrawal signs in morphine-dependent rhesus monkeys.

In the dose range of 4.0--32.0 mg/kg s.c., caffeine produced most of the signs which are commonly seen after the administration of naloxone (0.05 mg/kg s.c.) to morphine-dependent monkeys. The signs designated as lying on side or abdomen, avoiding contact, vocalizing, crawling or rolling, restlessness or pacing, tremors, retching, vomiting, coughing, vocalizing when abdomen palpated, rigid abdomen and salivation were noted. A randomized and blind experimental design, which included vehicle and positive (naloxone) controls was used. The significance of the differences between total scores for the whole syndrome was tested by the Mann-Whitney U-test. In preliminary studies in naive monkeys, caffeine was found to elicit some withdrawal signs but the results were equivocal. Na benzoate also elicited some withdrawal signs in morphine-dependent monkeys at 32.0 mg/kg s.c., but few signs were seen in naive monkeys. Caffeine was found to be approximately 10X more active than Na benzoate in inhibiting cAMP phosphodiesterase activity in a neuroblastoma cell whole homogenate assay. These results are consistent with the observations of Collier and Francis that morphine abstinence in rodents is associated with increased brain levels of cAMP.     

Modification by muscimol of naloxone-precipitated withdrawal symptoms in morphine-dependent mice

• 1.1. In morphine-dependent mice, muscimol, a GABAA agonist when given i.p. 30 min before naloxone, attenuated the naloxone-precipitated withdrawal symptoms of jumping, “wet dog” shakes and burrowing, but not body weight loss.
• 2.2. Muscimol produced a hypothermic effect which was further aggravated by naloxone.

     

Effects of antihistaminics on naloxone-induced withdrawal in morphine-dependent mice

Some histamine H1 (tripelennamine, diphenhydramine and cyclizine) and H2 (ranitidine and cimetidine) antagonists (1 and 10 mg/kg) were administered to morphine — dependent mice to evaluate the changes on naloxone-induced abstinence syndrome. When antihistaminics were administered 30 min before naloxone (1 mg/kg) on day 4 of morphine addiction, the two doses of the three H1 antagonists and the higher dose of ranitidine inhibited shaking behavior. Furthermore, the two doses of tripelennamine and the higher dose of diphenhydramine, cyclizine and cimetidine enhanced jumping behavior. When antihistaminics were administered chronically (during the 4 days of morphine addiction), tripelennamine, cyclizine and ranitidine (all at 10 mg/kg) inhibited shaking behavior. The three H1 antihistaminics used enhanced the number of jumps per mouse whereas ranitidine decreased this response. No significant changes were found in the rest of the withdrawal symptoms after the antihistaminics were administered. The participation of serotonergic and catecholaminergic mechanisms is discussed.     

莫索尼定对吗啡成瘾小鼠戒断反应的影响

莫索尼定 (ｍｏｘｏｎｉｄｉｎｅ ,Ｍｏｘ)是治疗高血压的新药 ,与第 1代中枢抗高血压药可乐定 (ｃｌｏｎｉｄｉｎｅ ,Ｃｌｏ)相比 ,无心动过缓和血压反跳现象。Ｍｏｘ和Ｃｌｏ均是作用于中枢去甲肾上腺素能神经Ｉ 受体的药物 ,但是Ｍｏｘ对α2 受体的激动作用显著弱于Ｃｌｏ[1] 。据文献报道 ,Ｃｌｏ用于脱毒治疗效果明显 ,其作用机制与中枢α2 受体有关[2 ] ,由于Ｃｌｏ对α2 受体和Ⅰ 受体缺乏选择性作用 ,不能排除其脱毒效应中Ⅰ 受体的参与。因此我们对Ｍｏｘ的戒毒治疗进行了研究。1　材料与方法1.1　药品　盐酸吗啡 (粉剂 ) ,东北第…     

The effects of ethanol,phenobarbital, and baclofen on ethanol withdrawal in the rhesus monkey

Physical dependence on ethanol was produced in four rhesus monkeys by IV ethanol administration every 8 h. Ethanol was administered on each occasion until the eyeblink reflex was lost. Evidence of physical dependence development, in the form of tremoring 8 h after an infusion, appeared on day 8 of chronic administration. Abrupt cessation of ethanol administration following 16 days of chronic administration was accompanied by moderate to severe tremoring, retching, vomiting, and one or more convulsions. Peak withdrawal occurred between 12 and 32 h after abrupt discontinuation of ethanol administration, and decreased over a period of 64–204 h. Ethanol dependence was then reinstated. Once every 3–4 days, ethanol was withheld for 16 h. Withdrawal signs were scored for the first 12 h of this period, and then a test dose of ethanol, phenobarbital, or baclofen was administered. Withdrawal or intoxication signs were scored over the next 4 h, at which time ethanol administration was resumed. Both ethanol and phenobarbital suppressed ethanol withdrawal sign in a dose-related manner, and produced dose-related intoxication. Baclofen was largely ineffective in reducing withdrawal-induced tremors, although it was capable of producing sedation of a different type than that produced by phenobarbital and ethanol.     

Peripheral withdrawal recruits distinct central nuclei in morphine-dependent rats

This study examined if brain pathways in morphine-dependent rats are activated by opioid withdrawal precipitated outside the central nervous system. Withdrawal precipitated with a peripherally acting quaternary opioid antagonist (naloxone methiodide) increased Fos expression but caused a more restricted pattern of neuronal activation than systemic withdrawal (precipitated with naloxone which enters the brain). There was no effect on locus coeruleus and significantly smaller increases in Fos neurons were produced in most other areas. However in the ventrolateral medulla (A1/C1 catecholamine neurons), nucleus of the solitary tract (A2/C2 catecholamine neurons), lateral parabrachial nucleus, supramamillary nucleus, bed nucleus of the stria terminalis, accumbens core and medial prefrontal cortex no differences in the withdrawal treatments were detected. We have shown that peripheral opioid withdrawal can affect central nervous system pathways.     

河豚毒素对大鼠和小鼠纳洛酮催促吗啡戒断症状的影响

通过建立吗啡 (Mor)依赖大鼠及小鼠模型 ,观察河豚毒素 (TTX ,大鼠 0 .0 0 3～ 0 .1μg·kg- 1·d- 1,im ,5d ;小鼠 0 .0 2～ 0 .2 μg·kg- 1·d- 1,ip ,2d)对纳洛酮 (Nal)催促戒断症状的预防及治疗作用 .结果表明TTX抑制戒断后大鼠体重丢失 ;明显抑制Mor依赖小鼠Nal催促后的跳台反应 ,并促进催促后小鼠体重的恢复 .证实TTX可显著抑制Mor依赖大鼠和小鼠Nal激发的戒断反应 ,其效果与可乐定相近 .在防治戒断症状的有效剂量范围内 ,TTX不影响麻醉大鼠的血压 ,呼吸和心率 ,也不影响尼古丁诱发的神经反射活动 ,对痛觉反应和中枢神经系统无明显抑制作用 .     

Verapamil prevents withdrawal excitation of oxytocin neurones in morphine-dependent rats

We investigated whether the full expression of morphine withdrawal excitation by supraoptic nucleus (SON) oxytocin neurones is a property of the neurones themselves or a partial function of their afferent inputs, by interrupting synaptic input activity via central administration of the L-type Ca(2+) channel blocker verapamil. In morphine-dependent rats, withdrawal-induced release of oxytocin from the posterior pituitary was suppressed by prior administration of intracerebroventricular (i.c.v.) verapamil (160 microg), as was release of oxytocin within the SON measured by microdialysis. During morphine withdrawal the increased electrical activity of SON neurones was also reduced both by i.c.v. verapamil and microdialysis application of verapamil or nifedipine into the SON. Oxytocin secretion evoked by electrical stimulation of the pituitary stalk was unaffected by i.c.v. verapamil suggesting a central site of action. To determine whether the inhibitory actions of verapamil were specific to morphine withdrawal, we also investigated the effects of verapamil on other oxytocin-secreting stimuli. I.C.V. verapamil given to morphine-na?ve rats abolished pituitary oxytocin release in response to activation of brainstem or rostral excitatory inputs by cholecystokinin (20 microg kg(-1), i.v.) and 1.5 M saline (4 ml kg(-1), i.p.) respectively, whilst in lactating rats, i.c.v. verapamil reduced suckling-induced release of oxytocin within the SON. These results suggest that verapamil has a central site of action on stimulated oxytocin release (including an action within the SON) and that both pre and post-synaptic L-type Ca(2+) channels are required for the full expression of morphine withdrawal in SON oxytocin neurones.