TRH对吗啡镇痛作用的影响及其对呼吸、循环和中枢神经系统的作用

本文就TRH与NAL拮抗吗啡类药物的镇痛、成瘾及制动作用作了比较研究,并观察了TRH对呼吸、循环及中枢神经系统的作用。结果发现TRH不能拮抗吗啡类的镇痛、成瘾及制动作用。TRH(10μg icv或5mg/kg iv)可显著升高正常动物平均动脉压,加快心率及呼吸。TRH腹腔注射可缩短戊巴比妥钠的睡眠时间,并呈一定剂量依赖关系。     

合成镇痛剂及拮抗剂的新进展

吗啡是阿片的主要成分,其镇痛作用确切,效果良好,但也有许多不良的副作用如呼吸抑制,便秘、昏睡、呕吐等,但最大的问题是容易成瘾及产生耐药性,因而受到麻醉品条例的严格控制。为了寻找不成瘾的镇痛剂,并减少吗啡的其它副作用,进行了大量的合成筛选及作用原理的研究工作,早期的工作大多围绕着用半合成方法改变吗啡结构。自从1939年度冷丁被合成并肯定其镇痛作用以来,特别是近廿年来,新镇痛剂研究的数量和质量都取得显著进展,但寻找不成瘾镇痛剂的任务还远未解决,随着新化合物的不断出现和新的药理作用的不断     

视上核催产素神经元在吗啡依赖中的作用

吗啡是一种疗效显著的麻醉性镇痛药,但长期以来吗啡的成瘾性一直困扰着人类,为了克服吗啡成瘾问题,人们做了大量的研究工作。目前,对吗啡依赖机制还没有完全认识,根治吗啡成瘾,尤其是解除吗啡的精神依赖性,仍是一大难题。催产素是一种垂体神经肽,它参与痛觉调制和加强阿片类物质的镇痛作用,并可影响药物成瘾性和学习记忆过程。近年的研究结果表明,催产素与吗啡依赖存在着密切联系,催产素可抑制吗啡耐受的形成过程,而吗啡及其类似物可抑制催产素释放。那么催产素神经元与吗啡依赖之间可能存在着怎样的联系呢？催产素神经元主要集中分布在下丘…     

强痛定成瘾三例报道

强痛定即“1-正丁酰基-4肉桂基-哌嗪盐酸盐”,为近年用于临床镇痛的新药。据报道强痛定系非麻醉性不成瘾的镇痛药,镇痛作用为吗啡1/3,比氨基比林强4～20倍,副作用少,故成瘾问题往往不被人们重视。我院使用强痛定1,400人次,三例成瘾,成瘾率为0.2%。成瘾患者均有药物依赖性,用药后有欣快感,一但停药则产生戒断症     

纳洛酮临床应用的研究进展——神经精神、内分泌、代谢和心血管系统方面

1960年Fishman 首先合成了纳洛酮(N-Allylynorexy Morphone;Naloxone 缩写N_x)。其结构虽似吗啡,但不成瘾,故不属麻醉药物禁限范围。N_x与具有双向激动-拮抗作用的药物如烯丙甲吗啡(Nalorphin);丙烯左吗喃(Levallorphan)和镇痛新(Pentazocine)等不同,N_x只具有拮抗中枢性麻醉药的作用。它极易通过血脑屏障,能较快地与内源性μ、K和σ三种阿片受体起竞争性拮抗作用,其中与μ受体亲合力最强。1961年Blumberg 报导N_x对镇痛有拮抗作用。近年来由于镇痛原理的研     

纳曲酮微球缓释制剂的药效学研究

本研究目的为观察纳曲酮微球缓释制剂抗吗啡镇痛和成瘾的药效学,药代动力学,组织相容性及生物降解性,为临床应用提供依据。通过小鼠热板法、大鼠甩尾法和吗啡依赖催促实验表明,纳曲酮微球缓释制剂单次皮下给药后对抗吗啡的镇痛作用和阻断小鼠吗啡躯体依赖形成的有效时间均达一个月以上,药代动力学研究证明,大鼠皮下给药有效血药浓度均能维持30天以上,注射局部的病理检查,无明显局部刺激反应,组织相容良好;在大鼠皮下微球约50天内完全降解。     

吗啡静脉自控镇痛时的剂量选择

目的研究不同剂量吗啡持续静脉推注用于自控镇痛的效果。方法选择90例开胸手术患者,ASAⅠ～Ⅱ级,随机分为3组,每组30例;A组吗啡0·02mg/(kg·h);B组:吗啡0·03mg/(kg·h);C组:0·01mg/(kg·h)吗啡 0·02μg/(kg·h)芬太尼。分别给予不同剂量吗啡进行静脉自控镇痛。结果吗啡 芬太尼组镇痛效果最好,不良反应最少。结论吗啡 芬太尼联用是比较理想的术后镇痛方案。     

野罂粟总生物碱镇痛作用

目的：研究野罂粟总生物碱（total alkaloids of Papaver nudicaul，TAPN）的镇痛作用特点。方法：采用小鼠热板法和大鼠电刺激甩尾法两种致痛模型研究TAPN镇痛作用特点。结果：小鼠热板法和大鼠电刺激甩尾法致病实验结果表明：ipTAPN具有明显的镇痛作用，其作用强度约为吗啡的1／5～1/4。单次给药的镇痛作用达峰时间与吗啡相似，均在20min以内，但镇痛作用持续时间明显长于吗啡，可达4h以上。与吗啡明显不同的是．TAPN的镇痛作用无耐受性。结论：TAPN具有明显的镇痛作用，作用强度弱于吗啡．约为吗啡的1／5-1/4，但镇痛作用维持时间明显长于吗啡，可持续4h以上．且其镇痛作用无耐受性。     

CCK-8对吗啡成瘾大鼠戒断症状及尾核内c-jun蛋白表达的影响

目的从行为学、形态学角度,初步研究了八肽胆囊收缩素(CCK-8)对吗啡成瘾大鼠戒断症状及尾核(Cd)内原癌基因c-jun蛋白表达的影响。方法采用动物行为学评估和免疫组化的方法,观察吗啡成瘾大鼠Cd内注入CCK-8(10mg.L-1,1μl)对c-jun蛋白表达和戒断症状的影响。结果①吗啡成瘾组大鼠戒断症状与生理盐水对照组大鼠行为学相比有差异;②吗啡成瘾大鼠在戒断24h时,Cd内注入CCK-8可使戒断症状降低,在戒断40h时戒断症状总分最明显;③单纯吗啡成瘾组大鼠Cd内c-jun蛋白表达与生理盐水对照组大鼠相比下降,而注入CCK-8后c-jun蛋白的表达上升。结论①成功建立吗啡成瘾大鼠模型;②Cd内注入CCK-8可使吗啡成瘾大鼠的戒断症状明显减少;③Cd内注射CCK-8可提高c-jun蛋白的表达。提示CCK-8能调控吗啡成瘾大鼠戒断症状的产生及Cd内c-jun蛋白的表达。     

急性吗啡依赖大鼠脑内G_(i2)蛋白的表达

目的研究急性吗啡成瘾后大鼠腹侧背盖区(Ventral tegmental area,VTA)、伏隔核(Nucleus accumbens,NAc)、前额皮质(Prefrontal cortex,PC)、海马(Hippocampus)及去甲肾上腺能神经中枢蓝斑(Locus coeruleus,LC)五个脑区Gi2蛋白的改变,探讨急性吗啡成瘾的可能机制。方法18只SD大鼠随机分为三组,每组6只,分别是急性吗啡成瘾组、急性吗啡戒断组、空白对照组。吗啡成瘾组和戒断组腹腔注射吗啡,直到吗啡成瘾模型建立。戒断组腹腔注射纳络酮5mg/kg,作用30min后断头处死各组大鼠。取出脑组织,进行冰冻切片。用免疫组化技术检测NAc、PC、LC、VTA和Hippocampus五个脑区相对Gi2蛋白水平。结果急性吗啡成瘾组和急性戒断组与空白对照组相比,NAc区Gi2蛋白水平有明显降低(P<0.01),其它脑区则未发现明显的改变。结论急性吗啡成瘾可引起大鼠脑内Gi2蛋白水平发生改变,NAc区Gi2蛋白水平有明显降低,其它脑区则未发现明显的改变。Gi2蛋白水平的改变可能是吗啡耐受和依赖潜在的分子机制。     

Inhibition of calcium/calmodulin-dependent protein kinase II in rat hippocampus attenuates morphine tolerance and dependence.

Learning and memory have been suggested to be important in the development of opiate addiction. Based on the recent findings that calcium/calmodulin-dependent protein kinase II (CaMKII) is essential in learning and memory processes, and morphine treatment increases CaMKII activity in hippocampus, the present study was undertaken to examine whether inhibition of hippocampal CaMKII prevents morphine tolerance and dependence. Here, we report that inhibition of CaMKII by intrahippocampal dentate gyrus administration of the specific inhibitors KN-62 and KN-93 to rats significantly attenuated the tolerance to the analgesic effect of morphine and the abstinence syndrome precipitated by opiate antagonist naloxone. In contrast, both KN-04 and KN-92, the inactive structural analogs of KN-62 and KN-93, failed to attenuate morphine tolerance and dependence, indicating that the observed effects of KN-62 and KN-93 are mediated through inhibition of CaMKII. Furthermore, administration of CaMKII antisense oligonucleotide into rat hippocampal dentate gyrus, which decreased the expression of CaMKII specifically, also attenuated morphine tolerance and dependence, while the corresponding sense oligonucleotide of CaMKII did not exhibit such inhibitory effect. Moreover, the KN-62 treatment abolished the rewarding properties of morphine as measured by the conditioned place preference. These results suggest that hippocampal CaMKII is critically involved in the development of morphine tolerance and dependence, and inhibition of this kinase may have some therapeutic benefit in the treatment of opiate tolerance and dependence.     

Morphine preference in rats previously morphine dependent

Morphine preference and tendency to relapse to morphine tolerance and dependence were studied in rats which were previously made morphine dependent. Tolerance to, and physical dependence on, morphine were initially produced by administration of increasing concentrations of morphine sulphate in 5% sucrose solution for 3 weeks. A test for drinking preference was performed 4 days after the rats had been successfully detoxified and showed no significant signs of morphine dependence. It was found that, while control animals drank only negligible amounts of morphine solution, previously morphine-dependent rats consumed significantly larger volumes of morphine solution and had recurrence of morphine tolerance and dependence. The present findings show that chronic administration of morphine in drinking fluid produces tolerance and physical dependence as well as addiction in rats; the latter definition is exemplified by these animals having a high tendency to relapse after successful drug withdrawal.     

The effects of D-histiding on the expression of morphine tolerance and physical dependence in mice

D-Histidine, administered in the 'wthdrawal' phase of morphine addiction, failed to modify the expression of tolerance and physical dependence in mice. L-Histidine, on the contrary, can enhance tolerance and inhibit physical dependence. Whole brain histamine is markedly increased by L-histidine administration, but only minimally by D-histidine. This confirms that the actions of L-histidine on morphine addiction are stereospecific, and so can be more confidently correlated with the increase in brain histamine levels produced by the natural amino acid precursor.     

The possible role of brain histamine and H1 and H2 receptors in the development of morphine tolerance and physical dependence in mice.

The possible role of brain histamine in the mechanisms of morphine tolerance and physical dependence is under investigation in mice. L-histidine and histamine, given during the 'withdrawal' phase, significantly increase tolerance to the analgesic effects of morphine but reduce the degree of physical dependence. Metiamide significantly inhibits tolerance but has no consistent effect on physical dependence. These results suggest that H2 receptors may be involved in the development of morphine tolerance. Mepyramine does not significantly affect tolerance, and with regard to dependence there is an effect only on body weight loss, which is increased. However, combined treatment with metiamide and mepyramine inhibits tolerance significantly more than metiamide alone; and withdrawal jumping is also reduced more significantly by combined treatment than by the separate administration of these drugs. It is suggested that brain histamine is definitely implicated in the mechanisms of the 'withdrawal' phase of morphine tolerance and physical dependence in mice, with H2 receptors probably playing the more important part.     

Evidence for the dissociation of morphine analgesia, tolerance and dependence

A single large dose of morphine produced profound analgesia accompanied by the development of tolerance and physical dependence. The tolerance developed acutely within 24 h and was further intensified, reaching a peak on the 5th day, then gradually disappeared. Partial or complete masking of morphine analgesia by naloxone inhibited the development of the acute, but could not prevent the development of the delayed, tolerance. These results suggest there are two kinds of tolerance and that the analgesic effect is separate from tolerance. Similarly, treatment with morphine produced physical dependence which was precipitated by naloxone. Unlike tolerance, dependence did not develop when morphine analgesia was completely masked by naloxone. The findings provide for the dissociation or morphine analgesia, tolerance and dependence.     

电针对吗啡慢性注射大鼠成瘾记忆的良性调节

目的:建立吗啡慢性注射大鼠成瘾记忆动物模型,观察电针对大鼠成瘾记忆的良性调节作用。方法:通过慢性皮下注射吗啡,或水迷宫平台上注射吗啡,伴高频声音线索,建立大鼠吗啡成瘾记忆模型,电针取穴为肾俞穴,频率2 Hz。结果:d12、d16和d20,吗啡组潜伏期和游泳总距离明显延长。多次电针肾俞穴治疗后,潜伏期和游泳总距离缩短,与吗啡组相比,具有显著性差异(P<0.05)。d16和d20吗啡线索组上平台时间和游泳总距离明显缩短,线索电针组延长上平台所需时间和游泳总距离。结论:电针肾俞穴可以改善慢性注射吗啡所受损的正常记忆能力,又能干预吗啡成瘾记忆,表现出双向调节的特点。     

Co-administration of dextromethorphan with morphine attenuates morphine rewarding effect and related dopamine releases at the nucleus accumbens

Morphine is one of the most effective analgesics in clinic to treat postoperative pain or cancer pain. A major drawback of its continuous use is the development of tolerance and dependence. In our previous study we found that a widely used antitussive agent in clinics, dextromethorphan [(DM); also known as a non-competitive N-methyl-d-aspartate (NMDA) antagonist], could prevent the development of morphine tolerance. In the present study, we further investigated its effect on morphine addiction. Conditioned place preference (CPP) test and behavioral sensitization of locomotor activity were used to investigate the drug-seeking related behaviors, which were in correlation with psychological dependence. Our results showed that co-administered DM was able to abolish completely the CPP effect induced by morphine, but had no effect on morphine-induced behavioral sensitization. By employing the microdialysis technique in free-moving animals, we also determined the extracellular level of dopamine and serotonin metabolites in the shell region of the nucleus accumbens (NAc) in its response to morphine with/without DM. A significant increase in dopamine metabolites following morphine administration was demonstrated in the NAc. This increase by morphine could be attenuated by co-administered DM, whereas DM itself did not show any effect. Based on our results, it is speculated that DM may effectively attenuate morphine-induced psychological dependence. Neurochemical analysis revealed that the effect of DM could be through its action on the dopaminergic mesolimbic pathway, which could be activated by morphine and attributed to the cause of rewarding.     

The ontogeny of opiate tolerance and withdrawal in infant rats

The acquisition of morphine analgesic tolerance was investigated in neonatal rats. Morphine was found to produce a potent analgesia, as measured by latency to retract a hindpaw from a 52 degree C hotplate, in rat pups as young as 1 day of age. Morphine analgesic tolerance, however, did not develop in rats until the third week of life. Rats given the same daily morphine regimen starting at 15 days of age or older showed rapid tolerance development. The data from four experiments indicate that experience with morphine prior to this age (Day 15) does not impact on the analgesic efficacy of the drug. Similarly, when morphine treatment was discontinued and the rats given a naloxone challenge, withdrawal symptoms were not observed in very young rats. Opiate withdrawal was first detected in rats that started their daily morphine treatment at 30 days of age and were then challenged with naloxone at 52 days of age. Therefore, two correlates of opiate addiction, tolerance and withdrawal, appear to be relatively late-developing phenomena in the rat.     

Analysis of opioid efficacy, tolerance, addiction and dependence from cell culture to human

Opioid agonists are the most effective treatment for pain, but their use is limited by side effects, tolerance and fears of addiction and dependence. A major goal of opioid research is to develop agonists that have high analgesic efficacy and a low profile for side effects, tolerance, addiction and dependence. Unfortunately, there is a serious lack of experimental data comparing the degree to which different opioids produce these effects in humans. In contrast, a wide range of experimental techniques from heterologous expression systems to behaviour assessment in whole animals have been developed to study these problems. The objective of this review is to describe and evaluate these techniques as they are used to study opioid efficacy, tolerance, addiction and dependence.