咪唑克生对吗啡镇痛、耐受和身体依赖的影响

目的:观察咪唑克生对吗啡镇痛及吗啡所致耐受和躯体依赖的影响.方法:采用小鼠醋酸扭体实验和55℃热板实验观察咪唑克生对基础痛阈及吗啡镇痛作用的影响;采用小鼠热辐射甩尾实验和小鼠55℃热板实验观察咪唑克生对吗啡耐受形成过程的影响;采用大鼠、小鼠身体依赖模型观察咪唑克生对吗啡所致身体依赖的影响.结果:咪唑克生(3-9mg/kg)能显著降低小鼠基础痛阈,抑制吗啡镇痛;加重吗啡所致耐受;诱发大、小鼠发生戒断综合征.结论:咪唑啉受体参与痛阈形成;咪唑克生能抑制吗啡镇痛,加重吗啡所致耐受;并诱发吗啡依赖性动物发生戒断综合征.     

胍丁胺对阿片受体环腺苷—磷酸信号转导系统代偿适应的影响

观察胍丁胺对阿片类所致脱敏和物质依赖的作用。方法：分别用放射配体结合实验和放免法测定γ－「３５Ｓ」－三磷鸟苷结合量和环腺苷一磷酸浓度。结果：在陛阿片类药物预处理的ＮＧ１０８－１５细胞实验中,胍丁胺使阿片类药物刺激「＾３５Ｓ」ＧＴＴＰ结合作用的增强３５％;合阿片类药物对ｃＡＭＰ抑制作用增强１１４．３％,使纳洛酮引起的吗啡物质依赖细胞ｃＡＭＰ超射幅度和对照组减小２１４．９％。     

咪唑啉类药物对星形胶质细胞白细胞介素-4分泌的作用

目的 观察咪唑啉类药物(咪唑克生,胍丁胺)调节大鼠星形胶质细胞IL-4分泌的影响.方法 10μg·mL-1脂多糖诱导培养后的星形胶质细胞,分为4组:对照组、咪唑克生组、胍丁胺组及地塞米松组.咪唑克生1 mmol·L-1;胍丁胺5 μmol·L-1;地塞米松1 μmol·L-1.于24 h收集上层培养液,用EILSA法测定4组的星形胶质细胞分泌IL-4水平.结果 用咪唑克生、胍丁胺、地塞米松处理后,IL-4分泌均增加.结论 咪唑克生、胍丁胺及地塞米松均促进星形胶质细胞Th2细胞因子分泌,使星形胶质细胞分泌的Th1/Th2细胞因子类型转换,起到免疫调节作用.     

胍丁胺对吗啡所致小鼠耐受和物质依赖的作用

目的 观察胍丁胺对吗啡所致耐受和依赖的作用。方法 分别在小鼠耐受和跳跃实验中观察胍丁胺抑制吗啡所致耐受和物质依赖的作用,结果：胍下胺０．１２５～２．５ｍｇ．ｋｇ＾－１剂量依赖性地阻止小鼠对吗啡耐受,用吗啡预处理小鼠使吗啡镇痛ＥＤ５０（２０．１,１４．４－２８．０ｍｇ．ｋｇ＾－１）与盐水组相比（６．３,５．１－７．８ｍｇ．ｋｇ＾－１）增加３倍以上,用胍丁胺和吗啡共同预处理小鼠则使吗啡丧失引直耐受的能     

胍丁胺-I1咪唑啉受体对μ阿片受体下调的影响及可能机制

目的:观察胍丁胺通过激活I1咪唑啉受体(I1R)对阿片预处理引起的μ阿片受体(MOR)下调的影响及可能的分子基础。方法:以CHO-μ和CHO-μ/IRAS(imidazoline receptor antisera-selected protein)细胞作为研究对象,用[3H]diprenorphine结合实验方法,确定胍丁胺-I1R作用系统对MOR下调的影响以及可能产生的分子基础。结果:在正常CHO-μ和CHO-μ/IRAS细胞中,DAMGO([D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin,1μmol·L-1)处理两细胞12h后均可出现MOR的下调,胍丁胺(1-100nmol·L-1)浓度依赖性地抑制CHO-μ/IRAS细胞中MOR的下调,而相同浓度胍丁胺在CHO-μ细胞中无此作用。胍丁胺这一作用能被I1R阻断剂依法克生(efaroxan,Efa)所阻断。DAMGO(1μmol·L-1)预处理两细胞30min后,MOR均发生内吞。胍丁胺(1nmol.L-1-1μmol·L-1)和DAMGO共同预处理两细胞30min,胍丁胺能浓度依赖性地抑制由DAMGO预处理引起的CHO-μ/IRAS细胞中MOR的内吞,而相同浓度胍丁胺对CHO-μ细胞中由DAMGO预处理引起的MOR的内吞无显著影响,且这一作用同样能被依法克生所阻断,提示胍丁胺通过激活I1R对DAMGO预处理引起的MOR内吞具有显著的抑制作用,这可能是胍丁胺-I1R作用系统抑制MOR下调的分子基础。结论:胍丁胺通过激活I1R抑制阿片激动剂诱导的MOR的内吞,进而进一步抑制MOR下调。     

内源性MAO—B抑制因子靛红对大鼠旋转行为的影响

靛红 (Isatin,ISA)在 6 -羟多巴胺损毁多巴胺神经元造成的大鼠旋转行为模型 ,急性投药 10 0μg· g-1ip显著抑制 L - DOPA诱发的旋转行为 (P<0 .0 1)。慢性 ig ISA 2 0 0μg· g-1连续给药 7d,对旋转行为也具有显著抑制作用 ,总转数减少 (P<0 .0 1)。因此 ISA对 L - DOPA诱发的旋转行为有抑制作用。     

人参皂甙对慢性酒精中毒大鼠脑组织内AchE和血清中MAO活性的影响

用50%白酒制作慢性酒精中毒大鼠模型,分别给大鼠以高、中、低剂量的人参皂甙溶液灌胃,测定大鼠脑组织内AchE和血清中MAO的活性,来探讨人参皂甙对大鼠脑组织内AchE和血清中MAO活性的影响,实验结果表明,高剂量人参皂甙能明显抑制慢性酒精中毒大鼠血清中MAO活性,提示人参皂甙对慢性酒精中毒所致的大鼠学习记忆障碍有改善作用。     

咪唑啉I_2受体研究进展

咪唑啉I2 受体是新近发现的一种咪唑啉受体 ,根据其与阿米洛利的亲和力可进一步将其分为I2A和I2B两个亚型 ,主要分布于肾、脑和肝细胞的线粒体外膜上 ,其内源性配体是胍丁胺。许多证据提示咪唑啉I2 受体与单胺氧化酶 B具有高度同源性 ,但其与配体的结合位点不同于该酶的催化位点。激活咪唑啉I2 受体可能产生神经元保护、抗血管平滑肌增生及调节阿片功能等多种药理作用。咪唑啉I2 受体与抑郁症、帕金森病、亨廷顿病、阿片成瘾及阿尔茨海默病等疾病的发生有关。     

Supersensitivity of cortical neurones of the rat to acetylcholine and L-glutamate following chronic morphine treatment

Summary The effect of microelectrophoretically applied L-glutamate and acetylcholine on discharge activity of cortical neurones was studied in naive and in morphine-tolerant/dependent rats. The thresholds for increase in discharge activity elicited by these 2 putative neurotransmitters were 3 times lower in the tolerant/dependent rats than in the naive rats, indicating the development of supersensitivity.     

Monoamine oxidase inhibitors and liver metabolism: Studies with isolated rat hepatocytes

Gluconeogenesis from a range of substrates in isolated liver cells from 48 hr starved rats was inhibited by clorgyline, l-deprenyl, pargyline, tranylcypromine, phenelzine and iproniazid. Generally similar results were seen in cells from fed and diabetic rats and in those from starved guinea pigs. These effects were reversed on removal of inhibitor by washing. Ureogenesis from alanine, but not β-oxidation, was also inhibited by similar concentrations of pargyline and tranylcypromine. The cell contents of malate, aspartate, oxoglutarate and phosphoenolpyruvate were decreased 50 per cent by pargyline. ATP was also decreased to a smaller extent. MAOIs3 increased oxygen uptake in mitochondria incubated with several substrates (state 4), an effect consistent with a degree of uncoupling of respiration and oxidative phosphorylation. These results are discussed in terms of a non-specific interaction with membrane lipids.     

胍丁胺抑制小鼠吗啡戒断与其抑制一氧化氮合酶的关系(英文)

目的:观察胍丁胺抑制纳洛酮引起小鼠吗啡戒断跳跃与其抑制一氧化氮合酶(NOS)的关系,方法:用测定[~3H]胍氨酸浓度的方法确定NOS活性,结果:在体外胍丁胺底物竞争性抑制正常和吗啡依赖小鼠小脑、端脑和丘脑NOS活性,纳洛酮引起吗啡依赖小鼠戒断跳跃和小脑、端脑、丘脑NOS活性升高,用吗啡和胍丁胺共同处理小鼠显著抑制纳洛酮促使小鼠戒断跳跃和NOS活性升高的作用,咪唑克生抑制胍丁胺的此作用,结论:胍丁胺对纳洛酮引起戒断跳跃的抑制作用与其通过激活咪唑啉受体和底物竞争性抑制NOS活性相关。     

Behaviourally-specific hyperdipsia in the non-deprived rat following acute morphine treatment

The effects of a range of doses of morphine sulphate on homecage food and water consumption were assessed in the non-deprived rat during the dark period of the light-dark cycle. Morphine (0.25–2.0 mg · kg^?1) produced a significant hyperdipsia in the absence of any concurrent alteration in food intake. The hyperdipsia occurred in the second hour of the test period. In larger doses (4 and 8 mg · kg^?1), morphine suppressed feeding and drinking behaviour. This depression of ingestive responses by larger doses of morphine was followed by a secondary hyperdipsia but not by a secondary elevation of food intake. The implications of the data for an endogenous opiate mechanism in the control of drinking responses are briefly considered.     

Agmatine: Biological role and therapeutic potentials in morphine analgesia and dependence

Agmatine is an amine that is formed by decarboxylation of L-arginine by the enzyme arginine decarboxylase (ADC) and hydrolyzed by the enzyme agmatinase to putrescine. Agmatine binds to several target receptors in the brain and has been proposed as a novel neuromodulator. In animal studies, agmatine potentiated morphine analgesia and reduced dependence/withdrawal. While the exact mechanism is not clear, the interactions with N-methyl-D-aspartate (NMDA) receptors, alpha2-adrenergic receptors, and intracellular cyclic adenosine monophosphate (cAMP) signaling have been proposed as possible targets. Like other monoamine transmitter molecules, agmatine is rapidly metabolized in the periphery and has poor penetration into the brain, which limits the use of agmatine itself as a therapeutic agent. However, the development of agmatinase inhibitors will offer a useful method to increase endogenous agmatine in the brain as a possible therapeutic approach to potentiate morphine analgesia and reduce dependence/withdrawal. This review provides a succinct discussion of the biological role/therapeutic potential of agmatine during morphine exposure/pain modulation, with an extensive amount of literature cited for further details.     

Effect of styrene on levels of serotonin,noradrenaline, dopamine and activity of acetyl cholinesterase and monoamine oxidase in rat brain

Oral intubation of styrene (1 ml/kg body weight daily) in adult male albino rats for 15 days produced a significant increase in serotonin and nor-adrenaline but no change in dopamine contents in brain. The brain of treated animals also showed a significant decrease in monoamine oxidase (MAO) but no change in acetyl cholinesterase (AChE) activity. The neurotoxic effects of styrene may be mediated through alterations in levels of these biogenic amines in the brain tissue.     

Does chronic morphine treatment induce a supersensitivity of dopamine receptors in rat brain?

These experiments were carried out to investigate whether chronic morphine treatment increases the sensitivity of dopamine receptors in rat brain. This was studied by considering apomorphine effectiveness in a) inducing stereotyped behaviour and b) decreasing the dopamine turnover in the striata.Acute morphine treatment slightly reduced stereotyped behaviour induced by l-Dopa and by apomorphine. In morphine-withdrawn rats, apomorphine was no more effective than saline in inducing stereotypies (sniffing, licking, gnawing). However, the ability of apomorphine to lower striatal dopamine turnover was increased in morphine-withdrawn rats. Despite these latter observations, chronic morphine treatment probably did not induce a supersensitivity of dopamine receptors in rat brain.Part of the results were presented at the VIth International Symposium on Clinical Pharmacology, Regensburg, Germany, Oct. 3–6, 1974.     

Effects of acute and chronic morphine treatment of calmodulin activity of rat brain

The cyclic AMP-phosphodiesterase assay was used to quantitate the amount of calmodulin activity in various brain areas of male rats treated acutely or chronically for 5 days with morphine. The acute treatment with morphine decreased calmodulin activity in the mitochondrial-synaptosomal P2 fraction of the striatum, midbrain, and thalamus but had no effect on the cerebellum, which contains a low density of opiate receptors. The decrease in calmodulin activity by morphine was dose-dependent and was blocked by the opiate antagonist naloxone. In contrast, chronic treatment of rats with morphine increased calmodulin activity in the mitochondrial-synaptosomal P2 of the striatum, midbrain, cerebral cortex, and thalamus. A highly sensitive Ca2+/Mg2+-ATPase assay was also used to quantitate the amount of calmodulin activity in subcellular fractions obtained from the striatum. Chronic morphine treatment caused a significant increase in calmodulin activity in the membrane containing microsomal, synaptosomal, and mitochondrial layers but only a small change in the layer that contained the soluble proteins and the synaptic vesicles. It is suggested that alteration of the content of calmodulin in specific subcellular sites may have a central role in opiate action and addiction via regulation of multiple calmodulin-sensitive biochemical pathways.