Tolerance to morphine-induced increases in [14C]catecholamine synthesis in mouse brain

Morphine sulfate increased the incorporation of carbon-14-labeled tyrosine into labeled catecholamines in the mouse brain. Tolerance was manifested by a shift to the right in the dose-response curve for morphine after mice were treated repeatedly with morphine. Naloxone, a specific morphine antagonist, also shifted the dose-response curve for morphine to the right.     

不同给药时间间隔对吗啡诱导小鼠条件性位置偏爱模型的影响

为比较不同给药时间间隔下,同等剂量的吗啡诱导条件性位置偏爱(CPP)模型的差异,为后续抗吗啡依赖药物的筛选奠定基础,本研究建立了不同时间间隔的吗啡诱导CPP模型,(1)吗啡组(24 h):连续4 d皮下注射,上午注射吗啡(5 mg·kg?1),下午注射生理盐水,吗啡给药间隔24 h,建立CPP模型;(2)吗啡组(48 ...     

Cellular adaptation to morphine in rats

The respiration of KCl-stimulated cortical slices of brain from control rats is markedly depressed by morphine, whereas the respiration of those from rats chronically dosed with morphine is unaffected. The results demonstrate an adaptation to morphine at the cellular level which is concomitant with the adaptation of the whole animal to morphine     

Paradoxical effects after microinjection of morphine in the periaqueductal gray matter in the rat

Paradoxical, concurrent hyper-and hyporeactivity of a profound nature to specific stimuli occurred when 10 micrograms of morphine was microinjected bilaterally into the periaqueductal gray matter of the rat brain. Both effects at this site were dose-dependent. The hyperreactivity (to previously neutral auditory and visual stimuli) was obtained only with intracerebrally injected morphine and never with intraperitoneally injected morphine or with other opiates administered either way. Rapid tolerance to toxic doses of morphine developed at this site, as well as cross tolerance of the hyporeactivity to painful stimuli between routes (intracerebral to intraperitoneal) of morphine administration. Both the hyper- and hyporeactivity were fully reversible by intracerebral injection of naloxone in the periaqueductal gray. Thus, the periaqueductal gray appears to be a major pathway for morphine action.     

Morphine: radioimmunoassay

The development of a radioimmunoassay for morphine is described.The hapten morphine is made antigenic by coupling it to a protein at the phenolic group of the molecule. Extremely low concentrations of morphine (0.5 nanogram) can be measured by this assay procedure.     

Morphine: single-dose tolerance

Rats show a significant degree of tolerance to a second dose of morphine, with the degree of tolerance increasing the longer the delay between the two doses of morphine. To measure the morphine effect a foot-shock attenuation procedure that allowed the animal to adjust the shock intensity was used in studying delays of up to 180 days.     

纳滤膜技术在吗啡提取物浓缩中的应用

以吗啡提取液为研究对象,研究纳滤膜技术在提取物浓缩中的应用。结果表明,经纳滤膜工艺能有效脱水达80%以上,主要有效成分吗啡收率达到99%以上,膜平均通量稳定在15 L/(m2·h),清洗后膜通量恢复至99%以上。     

Morphine tolerance, physical dependence, and synthesis of brain 5-hydroxytryptamine

Tolerance and physical dependence development to morphine in mice can be prevented by concomitant administration of cycloheximide. The fact that the rate of synthesis of brain 5-hydroxytryptamine (5HT) increases with tolerance to morphine suggests that the protein involved may be associated with 5HT synthesis. Inhibition of this synthesis with p-chlorophenylalanine markedly decreases tolerance and physical dependence development to morphine.     

Effect of deuteration of N--CH3 group on potency and enzymatic N-demethylation of morphine

Substitution of deuterium for the N-methyl hydrogens of morphine produced a significant reduction in the potency and lethality of morphine in mice regardless of the route of administration. There was no effect on the time of onset, maximal effect, or duration of action. N-demethylation by rat liver microsomal enzymes was characterized by a smaller reaction rate constant, a higher energy of activation, and a larger Michaelis constant with respect to the deuterated morphine. These findings indicated that deuteration of the N-methyl group of morphine not only caused reduction in potency, but also a reduction in the rate of oxidative N-demethylation, and a distinct weakening of the binding to the enzyme active centers.     

Disposition of morphine in man

The disposition of morphine was investigated by means of radioimmunoassay after a single intravenous dose (10 milligrams per 70 kilograms) was administered to 10 adult normal male subjects who had not received other drugs for 2 weeks preceding the study. A multiphasic decline in serum concentrations of morphine occurred. Detectable blood concentrations of morphine, or of a metabolite, or of both persisted for 48 hours after a single intravenous dose.     

Biosynthesis of the morphine alkaloids

Tracer experiments, supported throughout by the analogous chemical transformations, have firmly established the biosynthetic sequence tyrosine -->norlaudanosoline --> reticuline --> salutaridine --> salutaridinol-I -->thebaine --> codeine --> morphine in Papaver somniferum. In general, the farther a precursor lies along this sequence, the more efficient its conversion to morphine in the intact plant. Several intermediates remain to be discovered, such as those lying between tyrosine and norlaudanosoline and between thebaine and codeine. Proof that morphine is made only by the reticuline-salutaridine route is still lacking and would require a careful comparison of the rate of morphine synthesis with the turnover rates for the various intermediates. More importantly, detailed knowledge of the mechanism of each biochemical step can come only with isolation of the enzyme system involved. The chemical oxidation of (-)-reticuline, to give salutaridine, can only be accomplished in very low (0.02 percent) yield (15, 26), whereas, even with whole plants, the biological incorporation of reticuline into the morphine alkaloids can reach 8 percent (13). One would like to know just how an enzyme system directs the oxidative cyclization of reticuline in the desired sense. Kleinschmidt and Mothes and Fairbairn and Wassel (27) have shown that the latex isolated from opium poppies is capable of transforming tyrosine into morphine. Perhaps further work with opium latex will provide the key to the remaining problems of morphine biosynthesis.     

复方万年青胶囊联合美施康定治疗97例肺癌重度疼痛患者的临床观察

目的 观察复方万年青胶囊联合美施康定（硫酸吗啡缓释片）控制肺癌重度疼痛的效果。方法 回顾性调查97例肺癌重度疼痛患者,随机分为2组,对照组47例,采用美施康定治疗;试验组50例,采用复方万年青胶囊联合美施康定治疗,观察2组的抗癌痛效果、美施康定的人均维持日剂量、生活质量改善情况及不良反应发生情况。结果 与对照组相比,试验组抗癌痛效果较优（P<0.05）,美施康定的人均维持日剂量较小（P<0.05）,生活质量改善更明显（P<0.05）,毒副作用更小。结论 复方万年青胶囊联合美施康定治疗肺癌重度疼痛,能明显缓解癌痛,增强止痛效果,减轻不良反应,提高生活质量。     

吗啡对不同来源KM小鼠的镇痛、耐受和身体依赖性的比较

用吗啡对A、B、C3家实验动物繁育生产专业单位KM小鼠进行镇痛、耐受性和身体依赖性的比较实验。结果显示,A、B、C3家单位KM小鼠的利用率分别为70%、77%和81%,吗啡热板法镇痛ED50分别为3.611mg/kg、3.635mg/kg和5.096mg/kg,A单位KM小鼠吗啡镇痛起效最快,作用维持时间最长,C单位KM小鼠镇痛作用最弱。吗啡的耐受性实验结果表明,3家单位的KM小鼠之间没有差异,但是吗啡的身体依赖性实验结果表明,B、C单位KM小鼠与A单位小鼠之间有显著性差异(p<0.01)。结果提示,用吗啡对KM小鼠进行镇痛实验时,必须使用同一来源的动物,此外,加速我国KM小鼠的标准化研究迫在眉睫。     

Morphine-3-succinyl--bovine serum albumin: an immunogenic hapten-protein conjugate

Morphine-3-hemisuccinate was synthesized by reaction of morphine with succinic anhydride. This compound was conjugated to bovine serum albumin by the mixed anhydride method, and the degree of conjugation was determined by base hydrolysis of the conjugate, extraction, and measurement of free morphine. An average of 6.5 molecules of morphine were conjugated to each molecule of protein. Eleven rabbits immunized with varying doses of the conjugate were producing antibody 8 weeks later, as determined by a modification of the ammonium sulfate method, which measures primary binding of antigen by antibody.     

萘普生栓联合吗啡硬膜外镇痛用于剖宫产术后镇痛的临床观察

目的观察萘普生栓联合吗啡硬膜外镇痛在剖宫产术后镇痛效果。方法将123例剖宫产产妇随机分成萘普生栓联合吗啡硬膜外镇痛组(NM组,61例)和单纯吗啡硬膜外镇痛组(M组,62例),比较两组间术后4、8、12、24hVAS评分、以及24h内镇痛泵按压次数和不良反应发生情况。结果 NM组术后4、8、12、24hVAS评分、以及24h内镇痛泵按压次数均明显低于M组(P<0.01或0.05),两组间不良反应差异无统计学意义(P>0.05)。结论萘普生栓联合吗啡硬膜外镇痛在剖宫产术后镇痛效果明显,值得临床应用。     

Evidence for active immunity to morphine in mice

The serum from mice actively immunized with a morphine immunogen contained antibodies that could bind dihydromorphine. Morphine effects were diminished in these "immunized" mice, and the concentration of morphine in their plasma was altered.     

Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801.

The N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor is an important mediator of several forms of neural and behavioral plasticity. The present studies examined whether NMDA receptors might be involved in the development of opiate tolerance and dependence, two examples of behavioral plasticity. The noncompetitive NMDA receptor antagonist MK-801 attenuated the development of tolerance to the analgesic effect of morphine without affecting acute morphine analgesia. In addition, MK-801 attenuated the development of morphine dependence as assessed by naloxone-precipitated withdrawal. These results suggest that NMDA receptors may be important in the development of opiate tolerance and dependence.     

Anatomically distinct opiate receptor fields mediate reward and physical dependence

Rats never before exposed to opioids rapidly learned to press a lever for microinjections of morphine into the ventral tegmental area. Challenge by a narcotic antagonist produced no signs of physical dependence. Dependence was not seen after long-term morphine infusions into the ventral tegmentum but was seen after similar infusions into the periventricular gray region. Thus a major rewarding property of morphine is independent of the drug's ability to produce physical dependence. These data challenge models of drug addiction that propose physical dependence as necessary for the rewarding effects of opioids.     

Morphine: conditioned increases in self-administration in rhesus monkeys

Operant responding in three monkeys was maintained by intravenous presentations of morphine. Nalorphine produced reliable increases in morphine-reinforced responding. With successive daily nalorphine injections there was a decreased latency of self-administration responding for morphine, and substituted saline injections produced conditioned increases in morphine-reinforced responding.     

Drug history modifies the behavioral effects of pentobarbital

Behavior of squirrel monkeys, maintained by the termination of stimuli associated with electric shock, was suppressed by response-dependent shock delivery. The effects of pentobarbital on this behavior depended on whether monkeys had previously received morphine. In monkeys without experience with drugs, pentobarbital increased responding. In monkeys with recent experience with morphine, however, pentobarbital resulted in a smaller increase or decrease in responding. The rate-decreasing effects of pentobarbital after a history of morphine administration could be reversed by the administration of d-amphetamine. These findings suggest that the behavioral effects of abused drugs may depend on previous experience with other drugs, even when those drugs are from a different pharmacological class.