美施康定与奥施康定直肠给药治疗癌痛的对比研究

目的：观察比较吗啡控释片（美施康定）与羟考酮控释片（奥施康定）直肠给药治疗癌痛的效果。方法将136例晚期癌痛患者随机分为2组：吗啡组（66例）和羟考酮组（70例）。2组间临床资料差异无显著性（ P＞0.05）。2组分别给予吗啡控释片及羟考酮控释片直肠给药治疗癌痛,观察2组直肠给药起效时间及副反应。结果2组癌痛治疗药物起效时间长短差异有显著性（ P＜0．05）。2组癌痛治疗药物不良反应发生率：头晕、恶心呕吐、便秘,差异均有统计学意义（ P＜0．05）。结论盐酸羟考酮控释片直肠给药起效时间更短,而硫酸吗啡控释片直肠给药副反应更小。     

竹叶椒片对大肠杆菌所致大鼠慢性盆腔炎的治疗作用

目的:研究竹叶椒片对大肠杆菌所致大鼠慢性盆腔炎的治疗作用。方法:采用大肠杆菌O-B4标准菌株的菌液注入大鼠子宫内,制备大鼠慢性盆腔炎动物模型。大鼠分6组:假手术组、模型组、竹叶椒大、中、小剂量组和妇科千金片组,分别给予相应药物,每天ig 2次,连续21 d。然后测定大鼠免疫功能并进行大鼠子宫组织形态学观察。结果:给药组大鼠血清凝集素效价显著升高,淋巴细胞转化指数也明显提高,组织形态学观察发现给药组大鼠慢性盆腔炎病理改变明显减轻。结论:竹叶椒片对大肠杆菌所致大鼠慢性盆腔炎有明显治疗作用。     

清君饮戒毒效应的实验研究

研究观察中药制剂清君饮对动物药物依赖性的影响，用逐次逐日增加吗啡注射剂量的方法造成大鼠的吗啡依赖性模型后，又分别分为中药大，小剂量组，吗啡维持组，空白对照组，再给予腹腔注射纳洛酮给予催瘾，结果表明：中药能明显抑制成瘾大鼠的戒断症状。     

葛根素对局灶性脑缺血再灌注大鼠行为及病理改变的保护作用

目的:研究葛根素对大鼠局灶性脑缺血再灌注损伤的保护作用,并探讨其神经保护作用的机制。方法:Wistar大鼠分为3组:假手术组,模型组和给药组,采用局灶性脑缺血再灌注模型(即大脑中动脉栓塞法),预先给予葛根素,然后分别观察和检测脑组织形态学、脑组织含水量及神经功能障碍评分指标。结果:给药组与模型组相比,脑组织病理损害和水肿明显减轻,梗死面积减少,神经功能障碍评分明显降低。结论:葛根素对大鼠局灶性脑缺血再灌注损伤具有一定的保护作用。     

消炎痛栓用于剖宫产术后镇痛的效果观察

目的探讨消炎痛栓联合盐酸吗啡缓释片对剖宫产术后镇痛的临床效果。方法选择于我院行剖宫产的足月孕妇200例。随机分我两组,观察组:102例,术后给予消炎痛栓直肠给药和盐酸吗啡缓释片直肠给药;对照组:98例,术后仅给予盐酸吗啡缓释片直肠给药。结果经给药治疗,观察组镇痛效果明显好于对照组,差异有统计学意义(P<0.05)。其中观察组镇痛有效率为98.0%,对照组镇痛有效率为85.7%。两组患者不良反应的发生情况无明显差异,差异无统计学意义(P>0.05)。结论消炎痛栓联合盐酸吗啡缓释片对剖宫产术后镇痛的临床效果显著,副作用小。     

急性阿片耐受大鼠脊髓NMDA受体NR2A及NR2B亚基表达的改变

目的：了解大鼠短期多次应用芬太尼能否发生急性阿片耐受以及急性阿片耐受大鼠脊髓NMDA受体NR2A和NR2B亚基表达的改变。方法：24只体重为200-220g的雄性SD大鼠随机分为3组（n=8）：对照组（C）,生理盐水组（S）及芬太尼组（F）。F组大鼠给予皮下注射芬太尼30μg/kg,共4次,每两次注射之间间隔15min,S组大鼠以生理盐水代替芬太尼,C组大鼠未给药。给药前及给药结束后每30min以Von-Frey仪测定各组大鼠的机械刺激缩足阈值（paw withdrawal threshold,PWT）。当F组大鼠的PWT恢复到给药前基础水平时,各组大鼠均给予腹腔注射吗啡5mg/kg。随后仍每30min测定各组大鼠的PWT,直至F组大鼠的PWT再次回到基础水平。对各组大鼠不同时间点的PWT进行组内和组间比较。另24只体重为2000-220g的雄性SD大鼠分组及给药方法同前（分为C^＊、S^＊及F^＊组）,当F＊组大鼠的PWT首次恢复到基础值时,不给予吗啡,处死各组大鼠,取脊髓,以Western blotting方法测定NMDA受体NR2A及NR2B亚基的蛋白表达水平。结果：连续4次皮下注射芬太尼（F组）后大鼠首先表现为PWT较基础值显著升高,随后PWT降低到基础值以下,然后逐渐恢复至基础值水平,此时皮下注射吗啡后,吗啡的镇痛效果显著低于其他两组大鼠（S组,C组）。F^＊组大鼠脊髓的NR2B亚基表达水平显著高于C^＊组及S^＊组,各组大鼠脊髓的NR2A亚基表达水平的差异无统计学意义。结论：短期应用芬太尼可导致大鼠发生急性阿片耐受。急性阿片耐受大鼠的脊髓NMDA受体NR2B亚基表达水平显著升高,NR2A亚基表达水平无明显变化。     

吗啡预处理对脑缺血-再灌注后神经元凋亡、Bcl-2及Bax表达的影响

目的探讨吗啡预处理对大鼠脑缺血-再灌注损伤后神经元凋亡、Bel-2及Bax蛋白表达的影响。方法 Wistar大鼠32只随机分成假手术组、模型组、吗啡1mg·kg~(-1)组、吗啡7mg·kg~(-1)组,各8只。四动脉阻断法建立脑缺血模型。缺血前60min腹腔注射给药,假手术组和模型组给予生理盐水。脑缺血8min、再灌注24h后取大鼠的脑组织,HE染色观察海马区脑组织病理学改变、TUNEL法检测神经元凋亡、免疫组化法观察Bcl-2及Bax蛋白表达。结果吗啡预处理使海马神经元病理改变减轻、凋亡细胞数及Bax表达减少(P<0.01),而Bcl-2表达增加(P<0.01);且吗啡7mg·kg~(-1)组减少神经元凋亡及改善神经元病理变化的作用更为显著(P<0.01)。结论吗啡预处理可减少缺血-再灌注损伤后神经元凋亡,其作用机制可能与其影响Bcl-2和Bax蛋白表达有关。吗啡7mg·kg~(-1)预处理的保护作用更为显著。     

吗啡成瘾和应激诱导复发的大鼠脑内神经甾体水平的变化

目的 观察大鼠吗啡成瘾及应激诱导成瘾复发是否与脑组织神经甾体水平的变化有关。方法 给大鼠注射吗啡（5 mg·kg^-1·d^-1，ip, 18：00～20：00）并在条件性位置偏爱(CPP)箱中训练，每日1次，连续10 d，最后1次给药后24 h测试大鼠是否产生CPP。再经过7 d的自然消退期后，给予足底电击(0.5 mA, 0.5 s, 间隔40 s, 15 min)诱发大鼠CPP复发，电击后2 h 进行CPP测试。测试后立即取样，取样时间18：00～20：00，气相色谱-质谱联用技术测定大鼠脑组织神经甾体。结果 给予吗啡并训练10 d，大鼠形成明显的CPP，同时脑组织内神经甾体孕烯诺龙和别孕烯诺龙水平显著升高。经过7 d的自然消退后再给予足底电击可诱发大鼠CPP复发，脑组织神经甾体脱氢表雄酮和硫酸脱氢表雄酮水平显著升高。结论 大鼠吗啡成瘾及应激诱导成瘾复发过程可能与脑组织内源性神经甾体水平有关。     

吗啡依赖大鼠的脑电与心电观察

目的:观察吗啡依赖大鼠脑电、心电的改变。方法:用递增法制备吗啡依赖大鼠模型,自然戒断,在清醒状态下用RM6240系列多道生理信号采集处理系统记录脑电和心电。结果:吗啡依赖大鼠HR减慢,戒断后恢复;给药期α(8-14HZ)波较给药前显著增多,δ(1-4HZ)、θ(4-8HZ)、β(14-30HZ)与给药前相比无显著性差异;停药后与给药期相比δ波增加,α、θ波减少,但与给药前比较无统计学意义。β波给药前、给药期、停药后无明显改变。结论:吗啡依赖大鼠的脑电、心电均较给药前明显改变,戒断后的脑电、心电与给药前相比无显著差异。     

丁苯酞对大鼠神经细胞凋亡的保护作用及其机制研究

目的 探讨丁苯酞对大鼠神经细胞凋亡的保护作用及其机制研究.方法 选用90只SD大鼠,随机分为给药组、对照组和健康组,每组30只.对给药组和对照组大鼠使用10％水合氯醛麻醉(剂量为0.5 mL/100 g),麻醉完成后,对大鼠双侧海马区位置进行准确定位后,将浓度为5μL(1 μg/μL)Aβ1-42注入造模.将配置的丁苯酞与食用麻油混合配制成悬浊液.造模完成后,分别给予不同的处理方法,给药组按75 mg/kg比例对大鼠进行灌胃给药,1次/d.对照组按同等比例灌胃给予生理盐水,1次/d.健康组为正常健康组,不给予任何手术和药物处理.取大鼠脑组织分为两部分,一部分经固定、脱水、石蜡包埋后制得厚度约5μm切片.采用TUNEL染色法对脑组织细胞凋亡进行检测;并使用H&E染色法观察各组大鼠脑组织细胞;采用Western Blot法检测各组脑组织MAPK、Erk和P38的蛋白表达水平,并使用RT-PCR法检测MAPK、Erk和P38的mRNA表达水平.结果 30 d后,给药组大鼠脑组织细胞凋亡明显少于对照组及健康组.给药组大鼠MAPK、Erk和P38的蛋白表达水平明显低于对照组但高于正常健康组(P＜0.05).使用RT-PCR法检测MAPK、Erk和P38的mRNA表达水平发现,给药组大鼠MAPK、Erk和P38的mRNA水平明显低于对照组但高于正常健康组(P＜0.05).对照组大鼠达到学会标准次数与健康组比较明显升高(P＜0.05).与对照组比较,给药组大鼠达到学会标准次数明显降低(P＜0.05).结论 丁苯酞对Aβ1-42处理的大鼠脑组织细胞凋亡具有保护作用,通过抑制大鼠脑组织MAPK,Erk和P38的表达发挥作用.     

Brain neurotransmitter turnover correlated with morphine-seeking behavior of rats

Neurochemical substrates of intravenous opiate self-administration were investigated in rats using littermate controls for vehicle and passive morphine infusion. The rates of turnover of the putative neurotransmitters, dopamine, norepinephrine, serotonin, gamma-aminobutyric acid, aspartate and glutamate were concurrently measured in eleven brain regions of rats intravenously self-administering morphine and yoked-morphine or yoked-vehicle infused littermates. The passive infusion of morphine resulted in significant changes in the rates of turnover of the biogenic monoamine and amino acid neurotransmitters in six brain regions with the caudate nucleus-putamen-globus pallidus showing the most changes. The contingent infusion of morphine resulted in changes in utilization rates that were generally greater in both magnitude and number than the effects of the drug itself. Twenty-nine significant changes were observed in the self-administering group with most changes occurring in limbic structures. The neurotransmitter turnover rate changes resulting from contingent administration suggest that the drug administration environment is an important factor that should be considered in studies of interactions between drugs and neuronal systems.     

A novel nonpeptidic caspase-3/7 inhibitor, (S)-(+)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin reduces myocardial ischemic injury

A continuing challenge for studies in the neurobiology of drug abuse is to identify and characterize long-lived neuroadaptations that can trigger craving and relapse. We previously reported that rats that had actively self-administered methamphetamine for 5 weeks and were then withdrawn from methamphetamine for 24 h showed marked decreases in somatodendritic dopamine D(2) autoreceptor levels in the ventral tegmental area and median and dorsal part of the substantia nigra zona compacta with a corresponding down-regulation of dopamine D(1) receptors in the shell of the nucleus accumbens. The purpose of the present study was to determine whether neuroadaptive changes in dopamine receptors or transporters in the brains of rats withdrawn for 24 h from chronic methamphetamine self-administration are persistent changes that can be demonstrated long after withdrawal. A "yoked" procedure was used in which rats were tested simultaneously in groups of three, with only one rat actively self-administering methamphetamine while the other two received yoked injections of either methamphetamine or saline. In vitro quantitative autoradiography was used to determine densities of dopamine uptake sites and dopamine D(1) and D(2) receptors in different brain regions following 7- and 30-day periods of withdrawal from chronic methamphetamine self-administration. No changes in dopamine transporter and dopamine receptor numbers were detected in any brain region examined in rats self-administering methamphetamine compared with littermates receiving yoked infusions of either methamphetamine or saline. Thus, neuroadaptive changes in densities of dopamine receptors or transporters in certain brain areas may contribute to the reinforcing effects of methamphetamine during the acquisition and maintenance phases of self-administration, but do not appear to contribute to the long-lasting neuroadaptive effects of chronic methamphetamine self-administration, which may trigger craving and relapse.     

Opioid self-administration and rem sleep EEG power spectra

This study was designed to explore the possible existence of temporal electrophysiological changes in the central nervous system in dependent rats that were self-administering morphine, methadone, l-alpha-acetylmethadol (LAAM), nor-LAAM or dinor-LAAM. Adult, female, Sprague-Dawley rats were implanted with chronic cortical and temporalis muscle electrodes and intravenous (i.v.) cannulas for drug administration. Tolerance and physical dependence were induced by automatic hourly intravenous injections of increasing doses of morphine. Rats were then trained to lever press to selfadminister morphine on a fixed ratio 20 schedule of reinforcement. For some of the rats, morphine was then replaced with methadone, l-alpha-acetylmethadol (LAAM), nor-LAAM or dinor-LAAM. At least l week was allowed for the establishment of stabilized self-injection patterns. Samples of the EEG of successive rapid eye movement (REM) sleep episodes which occurred between self-injections were subjected to power spectral analyses using a Nicolet MED-80 system. During self-administration of these narcotic drugs, the first REM sleep episode following an injection had the faster peak EEG frequency. The peak EEG frequencies of the successive REM sleep episodes during an interinjection interval declined in a linear fashion towards the next injection. Differences in the slopes of the linear peak EEG frequency declines of the different narcotic drugs appear to correlate with differences in the pharmacokinetic profiles. These EEG changes are not related to lever pressing activity since analogous EEG frequency changes were seen in physically dependent rats receiving automatic morphine injections. The slowing in peak EEG frequencies may reflect a decline in brain levels of the respective drug leading to changes in the central nervous system that precede “drug-seeking behavior”.     

Intravenous self-administration of morphine and cocaine: a comparative study

The aim of the present study was to estimate differences between patterns of morphine and cocaine use in Sprague-Dawley rats. This was done by first developing a set of conditions under which both drugs would be consistently self-administered over time. Subsequently rats were studied in groups of three, with only one rat actively self-administering morphine or cocaine while others two receiving yoked injections of either the drug or saline. With the exception of the 0.056, 0.1, 0.3 and 1.0 mg/kg/inj. training-dose regimens, intravenous (i..v.)self-administration of morphine was acquired at the dose of 0.56 mg/kg/inj. and subsequently maintained by rats. In contrast to morphine self-administration, rats rapidly acquired cocaine self-administration behavior at either the 0.3 or 0.56 injection dose and showed typical inverted U-shaped dose-response curves with maximal responding occurring at the injection dose of 0.3 mg/kg. With the "yoked" pairs of subjects, the rate of responding of the animal actually self-administering the drug was significantly higher than that of a paired animal which passively received injection whenever the first animal self-administered the drug. Thus, both morphine and cocaine served as a positive reinforcer of self-administration behavior under the fixed ratio 5 schedule of reinforcement. However, the 0.56 mg/kg injection dose of morphine resulted in an acquisition curve that was markedly, temporally delayed relative to the injection dose of cocaine. Finally, cocaine maintained higher rates of responding for its delivery than morphine. These differences between self-administration patterns of morphine and cocaine may provide significant information about the nature of drug reinforcement and dependence.     

Modulation of the endogenous opioid system after morphine self-administration and during its extinction: a study in Lewis and Fischer 344 rats

Lewis (LEW) and Fischer 344 (F344) rats show differential morphine self-administration rates. In this study, after animals of both strains self-administered morphine (1mg/kg) or extinguished this behaviour for 3, 7 or 15days, we measured the binding to, and functional state of mu opioid receptors (MORs) as well as proenkephalin (PENK) mRNA content in several brain regions. The results showed that in most brain areas: 1) LEW rats had less binding to MORs in basal conditions than F344 rats; 2) after morphine self-administration, either one of the strains or both (depending on the brain area) showed increased levels of binding to MORs as compared to basal groups; and 3) these binding levels in morphine self-administration animals came down in each extinction group. Moreover, F344 rats exhibited, in general, an increased functionality of MORs after morphine self-administration, as compared to basal groups, which also went down during extinction. Finally, the basal content of PENK mRNA was lower in LEW rats than in F344 rats and it decreased more after self-administration; during extinction, the levels of PENK mRNA got normalized in this strain. This differential modulation of the endogenous opioid system might be related to the different rates of morphine self-administration behavior exhibited by both inbred rat strains.     

大鼠弥漫性脑损伤模型制作及伤后病理生理变化

目的 复制大鼠弥漫性脑损伤模型,观察伤后病理生理变化.方法 参照Marmarou致伤装置进行改造,采用不同冲击力(80 cm、450 g,120 cm、450 g和180 cm、400 g)打击大鼠头部,制成闭合性弥漫性脑损伤动物模型,观察伤后动物神经体征、生命体征、感觉运动功能及脑组织病理形态学变化.结果 不同冲击力作用下,大鼠伤后神经系统体征、生命体征及感觉运动功能均明显改变.形态学检查证实,不同冲击力下大鼠脑组织均存在弥漫性脑损伤特征,而且随着冲击力增加,伤后病理生理变化更明显(均P＜0.05).结论 成功复制大鼠不同程度弥漫性脑损伤模型,在120 cm、450 g冲击力下动物伤后死亡率低且病理变化典型,适用于弥漫性脑损伤的相关研究.     

Chronic opioid exposure produces increased heroin self-administration in rats

The purpose of this study was to determine the significance of chronic opioid exposure on the level of heroin self-administration in the rat. Rats were divided into morphine (M, subcutaneous morphine pellets) and placebo (P, subcutaneous placebo pellets) groups and self-administered several different doses of heroin during daily limited access 1-h sessions and prolonged access 8-h sessions. No effects on heroin self-administration occurred when the rats were implanted with morphine pellets and allowed to self-administer heroin in a limited access paradigm (1-h group). However, rats with morphine pellet implantation showed a rapid escalation (Days 0-3 post-pellet) in heroin self-administration in the more prolonged access group (8 h group) compared to placebo-pelleted animals also with 8-h access. Ultimately, placebo-pelleted 8-h exposed animals showed an escalation in heroin self-administration but this effect was delayed until Days 16-18 post-pellet. These results suggest that passive administration of morphine sufficient to produce and maintain dependence facilitates escalation in heroin intake.     

18-Methoxycoronaridine acts in the medial habenula and/or interpeduncular nucleus to decrease morphine self-administration in rats

The novel iboga alkaloid congener 18-methoxycoronaridine (18-MC) is a putative anti-addictive agent that has been shown, in rats, to decrease the self-administration of morphine and other drugs of abuse. Previous work has established that 18-MC is a potent antagonist at alpha3beta4 nicotinic receptors. Because alpha3beta4 nicotinic receptors in the brain are preferentially located in the medial habenula and the interpeduncular nucleus, the present study was conducted to determine if 18-MC could act in these brain areas to modulate morphine self-administration in rats. Local administration of 18-MC into either the medial habenula or the interpeduncular area decreased morphine self-administration while having no effect on responding for a non-drug reinforcer (sucrose). Similar results were produced by local administration into the same brain areas of two other alpha3beta4 nicotinic antagonists, mecamylamine and alpha-conotoxin AuIB. Local administration of 18-MC into the ventral tegmental area had no effect on morphine self-administration. These and other data are consistent with the hypothesis that 18-MC decreases morphine self-administration by blocking alpha3beta4 nicotinic receptors in the habenulo-interpeduncular pathway.     

Characteristics of chronic self-administration of morphine by dogs

Each of five dogs that had been trained to chronically self-administer IV morphine was tested with changes in the morphine dose from the baseline dose (1 mg/kg/infusion) to 0.125, 0.5, or 2 mg/kg/infusion, and with passive administration of the usual daily morphine intake while either continuing the morphine self-administration at the baseline dose or changing the self-administered solution to saline. Each treatment lasted 5 weeks. Results indicated that there is a significant negative regression of response on dose, and chronic self-administration of morphine is not entirely accounted for by a need to avoid abstinence or to obtain a direct drug effect. A third element, which may be an acquired need to obtain a response-contingent drug effect, is necessary to account for the chronic self-administration of morphine by the dog.     

Drug-seeking behavior in the dog: lack of effect of prior passive dependence on morphine

Twelve dogs were made dependent on morphine (20 mg/kg per 24 hours) by intravenous passive administration of the drug. Six were gradually withdrawn and six were withdrawn abruptly. Subsequent tests for self-administration of morphine began within 8 to 18 weeks after morphine was last administered passively. Morphine was available for self-administration at several unit dose levels for 8 weeks. In comparison with control dogs administered with saline, there was no evidence that prior dependence on morphine influences subsequent self-administration of morphine, or that morphine is a primary reinforcer for dogs. Possible implications of these and related observations are discussed.