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.     

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.     

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.     

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 ...     

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.     

Blood-brain barrier: penetration of morphine, codeine, heroin, and methadone after carotid injection

Labeled morphine, codeine, heroin, or methadone was injected as a bolus into the common carotid artery of the rat, and the rat was decapitated 15 seconds later. The brain uptake of the drug was calculated by measurement of the brain content of the drug as a percentage of a labeled, highly diffusible reference substance simultaneously injected. The uptake of morphine was below measurability; the uptake of codeine was 24 percent; heroin, 68 percent; and methadone, 42 percent. Brain uptakes of morphine and codeine were also studied after intravenous injection and correlated well with uptakes after carotid injection; the uptake of codeine being nearly complete by 30 seconds. These studies indicate that brain uptake of certain of these drugs is very rapid and that uptake of heroin injected intravenously is probably limited by the regional flow of blood in the brain. The possible relation of this rapid penetration of the blood-brain barrier by heroin to its strongly addictive properties is discussed.     

Excitatory and inhibitory effects of opiates in the rat vas deferens: a dual mechanism of opiate action

Both natural (-)-morphine and its unnatural enantiomer (+)-morphine exert an excitatory action on electrically stimulated contractions of rat vas deferens. Preexposure to (-)-morphine results in cross-tolerance to the inhibitory action of beta-endorphin. (-)-Naloxone and its stereoisomer (+)-naloxone also exert an excitatory action, but only (-)-naloxone bocks the inhibtory action of beta-endorphin. Thus morphine exerts a dual action on a peripheral organ: one an inhibitory action mediated by the stereospecific endorphin receptor that is blocked stereospecifically by naloxone, the other an excitatory action mediated by a nonstereospecific receptor that is not blocked by naloxone. The opiate abstinence syndrome is seen as due to the unmasking of the excitatory action of opiates when its concomitant inhibitory influence is removed by selective blockade by naloxone or weakened by selective tolerance. The view that the rat vas deferens is devoid of morphine receptors is now seen as arising from a reverse example of morphine's dual action: the masking of the inhibitory action of morphine by its concomitant and more potent excitatory action.     

A functional role for an opiate system in snail thermal behavior

The terrestrial snail Cepaea nemoralis, when placed on a 40 degrees C hot plate, lifts the anterior portion of its foot. The latency of this response is influenced by morphine and by naloxone in a dose-dependent and time-dependent manner. Morphine increases the time taken to respond, whereas naloxone reduces it. Furthermore, naloxone abolishes the effect of morphine. These results indicate that an opiate system may have a role in this behavior, which resembles that reported in vertebrates.     

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.     

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.     

Enhanced morphine analgesia in mice lacking beta-arrestin 2

The ability of morphine to alleviate pain is mediated through a heterotrimeric guanine nucleotide binding protein (G protein)-coupled heptahelical receptor (GPCR), the mu opioid receptor (muOR). The efficiency of GPCR signaling is tightly regulated and ultimately limited by the coordinated phosphorylation of the receptors by specific GPCR kinases and the subsequent interaction of the phosphorylated receptors with beta-arrestin 1 and beta-arrestin 2. Functional deletion of the beta-arrestin 2 gene in mice resulted in remarkable potentiation and prolongation of the analgesic effect of morphine, suggesting that muOR desensitization was impaired. These results provide evidence in vivo for the physiological importance of beta-arrestin 2 in regulating the function of a specific GPCR, the muOR. Moreover, they suggest that inhibition of beta-arrestin 2 function might lead to enhanced analgesic effectiveness of morphine and provide potential new avenues for the study and treatment of pain, narcotic tolerance, and dependence.     

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.     

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.     

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。     

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.     

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.     

Morphiceptin (NH4-tyr-pro-phe-pro-COHN2): a potent and specific agonist for morphine (mu) receptors

The synthetic peptide NH2-Tyr-Pro-Phe-Pro-CONH2 (morphiceptin), which is the amide of a fragment of the milk protein beta-casein, has morphinelike activities and is highly specific for morphine (mu) receptors but not for enkephalin (delta) receptors. It is as active as morphine in the guinea pig ileum but much less active in the mouse and rat vas deferens. The discovery of this specific morphine receptor ligand substantiates the hypothesis of multiple opiate receptors. The ligand, which may be of physiological significance since a very similar, or identical, activity can be detected in enzymatic digests of beta-casein, may prove useful for further investigation of the functions of opiate receptor subtypes.     

Growth retardation in offspring of female rats treated with morphine prior to conception

Treatment of female rats with morphine sulfate for 5(1/2) or 10 days, prior to drug withdrawal for 5 days and subsequent mating, results in retarded growth of offspring. The effect is not present at birth but appears at 3 to 4 weeks of age. It occurs even though offspring are not exposed to morphine in utero or postnatally. It is not eliminated by cross-fostering and is apparently of prenatal origin     

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。