Endogenous orphanin FQ: evidence for a role in the modulation of electroacupuncture analgesia and the development of tolerance to analgesia produced by morphine and electroacupuncture

1. Our previous work has demonstrated that exogenously administered orphanin FQ (OFQ) antagonizes morphine analgesia and electroacupuncture analgesia (EAA) in the brain and potentiates morphine analgesia and EAA in the spinal cord of the rat. In the present study we evaluated the role of endogenously released OFQ in the development of tolerance to morphine and electroacupuncture (EA) and the analgesia produced by electroacupuncture, by use of the IgG fraction of an anti-OFQ antibody (OFQ-Ab) microinjected into the rat central nervous system (CNS).
2. EAA was produced by stimulating rats at a frequency of 100 Hz. Rats were classified as either high responders (HR) or low responders (LR) based on the analgesic effects of EA. LRs could be converted into HRs by the intracerebroventricular (i.c.v.) microinjection of OFQ-Ab at both 1 : 1 and 1 : 10 dilutions but not 1 : 100. HRs could be changed into LRs by the intrathecal (i.t.) injection of OFQ-Ab at both 1 : 1 and 1 : 10 dilutions, but not 1 : 100.
3. Acute morphine tolerance was induced in rats by repeated subcutaneous (s.c.) injections of morphine (5 mg  kg, every 2 h) for 16 h. When injected i.c.v. the OFQ-Ab (1 : 1 dilution) had no effect on the development of acute morphine tolerance.
4. Chronic morphine tolerance was produced in rats by repeated injection of morphine (5–60 mg  kg, s.c., 3× a day) for 6 days. I.c.v. injection of OFQ-Ab (1 : 1 dilution) reversed this type of morphine tolerance in rats by 50% (P<0.01).
5. Acute tolerance to the analgesia produced by EA developed after 6 h of continuous (100 Hz, 3mA) stimulation. This tolerance was almost completely reversed by the i.c.v. injection of OFQ-Ab (1 : 1 dilution) (P<0.05).
6. Chronic tolerance to the analgesic effect of EA was produced by repeatedly administering increasing current (1, 2 and 3 mA, each lasting for 10 min, for a total of 30 min) at a frequency of 100 Hz once a day for 6 days. I.c.v. injection of OFQ-Ab (1 : 1 dilution) reversed this kind of tolerance by 50% (P<0.01).
7. Together these results suggest that 100 Hz EA may enhance the release of endogenous OFQ in the CNS of the rat, which in turn may act to antagonize EA-produced analgesia in the brain but potentiate EA produced analgesia in the spinal cord. Therefore, OFQ appears to play an important role in the development of tolerance to the analgesic effects produced by EA.
8. The mechanisms underlying the development of acute morphine tolerance and chronic morphine tolerance appear to be different. Central OFQ may play an important role in the development of tolerance after chronic morphine administration.

     

Intragastric drug self-administration by rats exposed successively to morphine and ethanol

Male Sprague-Dawley rats were implanted with intragastric cannulas for self-administration of drug solutions by bar-pressing on a continuous reinforcement schedule in 10-hour daily sessions. Similar levels of responding were observed for doses per infusion of 3.0 mg/kg morphine sulfate and 25 mg/kg ethanol in separate groups of rats. When rats that showed self-administration of a morphine solution over a 5-day period were then given access instead to ethanol for 5 days, the number of infusions taken did not deviate significantly between the two periods. However, rats selected from a small minority that failed to take morphine under these conditions also failed to manifest ethanol self-administration behavior. The data can be seen to support a possible concurrence or similarity between innate factors determining acceptance or rejection of morphine and ethanol as objects of self-administration behavior.     

Effects of morphine on methotrexate disposition in mice

1. Morphine has been shown to slow the renal excretion of other drugs. The present study in mice evaluated the effects of morphine on the disposition of methotrexate (MTX), an antimetabolite eliminated by the kidneys. 2. Mice were injected with morphine (20 mg/kg) or saline s.c. After 30 min, 20-80 mg/kg MTX was injected i.v. Blood and urine samples were assayed for MTX by HPLC. 3. Morphine reduced plasma clearance (CL) of MTX from 0.147 +/- 0.015 to 0.061 +/- 0.009 mL/min per g bodyweight (P < 0.01). The area under the plasma concentration-time curve (AUC(0- infinity )) was raised by morphine from 151 +/- 18 to 369 +/- 36 micro g.mL per min (P < 0.01). Without morphine administration, 22-27% of an MTX dose was excreted into the urine in 30 min. The corresponding fractions excreted into the urine after morphine were reduced to 15-18% (P < 0.01). 4. Plasma levels of MTX administered intravenously to mice are elevated by the concomitant administration of morphine, which reduces renal elimination of MTX.     

The effect of nitric oxide synthase blockade on responses to morphine in rat aortic rings

1 It has been suggested that opioids may play an indirect role in the regulation of the peripheral circulation through the control of nitric oxide (NO) release in vascular tissue. The current study was undertaken to investigate the effect of nitric oxide synthase (NOS) blockade on responses to morphine in phenylephrine (PE)- or KCl-precontracted rat aortic rings. 2 Morphine (3 x 10(-8) - 3 x 10(-5) M) administration did not cause any significant effect on basal tonus of endothelium-intact or endothelium-denuded preparations. Morphine produced concentration-dependent relaxation responses in endothelium-intact as well as in endothelium-denuded rat aortic rings precontracted by PE or KCl. Removal of endothelium did not significantly alter the relaxation responses to morphine. 3 The relaxant responses to morphine were significantly and partially inhibited by pretreatment of tissues with naloxone (NAL, 3 x 10(-5) M) for 5 min. The inhibitory effect of NAL on relaxant responses to morphine in PE- or KCl-precontracted rings did not differ significantly between endothelium-intact and endothelium-denuded preparations. 4 Incubation of endothelium-intact or endothelium-denuded rat aortic rings with NOS inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME, 10(-4) M) for 20 min did not cause a significant inhibition on relaxation responses to morphine. 5 These findings confirmed the presence of opiate receptors in rat thoracic aorta, but suggested that mechanisms other than NO release play a role in the relaxant effect of morphine on rat aortic rings.     

东莨菪碱和毒扁豆碱对吗啡训练大鼠空间学习的影响

目的 :研究吗啡训练大鼠的空间学习障碍与胆碱能系统的关系。方法 :ip吗啡和其他药品 ;通过Morris水迷宫任务检测药物对吗啡训练大鼠空间学习的影响。结果 :10mg·kg- 1 的吗啡对大鼠学习空间任务具有显著的抑制作用 ;10mg·kg- 1 吗啡和 3mg·kg- 1 东莨菪碱联合给药 ,对大鼠学习空间任务的损害更加严重 ;0 .1mg·kg- 1 毒扁豆碱能够降低 10mg·kg- 1 吗啡对大鼠空间学习的影响。结论 :吗啡对学习空间任务的影响机制之一是通过降低胆碱能系统的功能水平实现的     

Conditioned rewarding effects of morphine and methadone in mice pre-exposed to cocaine

BackgroundMethadone is widely accepted as the most effective treatment of opioid dependence. However, clinical observations indicate that the medication is less effective in individuals abusing cocaine. Diminished therapeutic efficacy of methadone in cocaine users is intriguing, but its mechanism has not been studied.MethodsHere, the conditioned place preference (CPP) procedure was used to examine the effects of the dose, number of conditioning sessions and pre-exposure to cocaine on the rewarding effects of morphine and methadone. Vehicle-pre-exposed and cocainesensitized mice (five injections of 10 mg/kg over 16 days) were conditioned using methadone (0, 0.1, 0.5, 3, and 5 mg/kg) or morphine (0, 1, and 10 mg/kg). Place preference was measured after one and again after two additional conditioning sessions.ResultsAs expected, morphine at 10 mg/kg produced CPP following just one conditioning session. While a single conditioning session with 1 mg/kg of morphine produced no CPP, the rewarding effect became apparent following two additional conditioning sessions as well as in mice pre-exposed to cocaine. Methadone produced CPP following one conditioning session at doses of 0.5, 3 and 5 mg/kg. However, unlike with morphine, methadone's rewarding effect was not enhanced by two additional conditioning sessions or by pre-exposure with cocaine.ConclusionsPrior exposure to cocaine increases unconditioned motivational effects of morphine but not of methadone.     

不同时间吗啡预处理对小鼠局灶性脑缺血损伤的保护作用

目的观察吗啡预处理对小鼠局灶性脑缺血损伤的保护作用并寻找有效预处理的产生时间。方法健康雄性BALB/c小鼠56只,随机分为假手术组（Sham组,n=8）、脑中动脉栓塞组（MCAO组,n=8）和吗啡预处理组（MP组,n=40）,吗啡预处理组又分为5个亚组,分别于预处理后0.5、12、24、48、72h行脑中动脉栓塞,每组8只。缺血后6h,通过神经功能评分、测定脑梗死面积及脑水肿率,观察吗啡预处理对小鼠局灶性脑缺血损伤的作用。结果与MCAO组比较,吗啡预处理能明显改善12h及24h组小鼠神经功能评分,减少脑梗死面积及水肿率（P〈0.05）,而0.5、48、72h时点则未见明显变化（P〉0.05）。结论吗啡预处理能减轻小鼠局灶性脑缺血损伤,其保护作用可能存在时间效应。     

Pharmacokinetic and pharmacodynamic study of morphine and morphine 6‐glucuronide after oral and intravenous administration of morphine in children with cancer

The aim of this study was to characterize the pharmacokinetics and pharmacodynamics of morphine and morphine 6‐glucuronide (M6G) in children with cancer. Serum concentrations of morphine and M6G in children who received single oral or short term continuous intravenous morphine were determined by HPLC and ELISA assays, respectively. The serum C_max of morphine and M6G after i.v. morphine administration was 560.5 and 309.0 nM and the T_max was 61 and 65 min, respectively. The elimination half‐life was 140.0 and 328.7 min, respectively. After oral administration of morphine, the serum C_max of morphine and M6G was 408.34 and 256.3 nM and the T_max was 40.0 and 60 min, respectively. The half‐life was 131.0 and 325.8 min, respectively. The side effects were: drowsiness (100%), nausea and/or vomiting (57%), pruritus (28%) and urinary retention (14%). There were no reports of respiratory complications. This study showed that pharmacokinetics factors of morphine and M6G in children were significantly different from adults. Therefore the required dose for children should be different from that of adults and should be based on studies performed on children rather than on studies on adults. Some adverse effects, particularly nausea and pruritus, may be commoner than is usually thought, while others, particularly respiratory problems did not occur. Copyright © 2009 John Wiley & Sons, Ltd.     

甲氧氯普胺对小鼠吗啡身体依赖性的影响

目的·· :观察甲氧氯普胺对吗啡身体依赖性的影响。方法·· :皮下注射盐酸吗啡建立吗啡依赖小鼠模型,以纳洛酮催促戒断症状。分别在建立吗啡依赖模型前或后给予不同剂量的甲氧氯普胺,观察其预防性给药和急性给药产生的影响。结果·· :甲氧氯普胺急性给药(20 -80mg·kg-1,ip)吗啡依赖小鼠跳跃次数显著减少 ,体重下降加剧 ;预防性给药 (5-20mg·kg-1,ip)小鼠跳跃次数减少 ,但无统计学意义 ,体重下降有显著性改善。结论·· :甲氧氯普胺可缓解吗啡依赖小鼠的部分戒断症状,在一定程度上抑制吗啡身体依赖的形成。     

Effects of quinidine on antinociception and pharmacokinetics of morphine in rats

Aim The aim of this study was to investigate the effect of quinidine, a P‐glycoprotein inhibitor, on the pharmacokinetics and pharmacodynamics of morphine in rats. Methods Rats were given morphine (30 mg/kg p.o. or 30 mg/kg over 10 min i.v.) 30 min after pretreatment with quinidine (30 mg/kg p.o.). Antinociceptive effects were determined using the tail immersion test. Concentrations of morphine in plasma and brain were also determined. Key findings The antinociception of morphine was significantly enhanced by oral administration of quinidine, with a 3.1‐fold greater area under the effect–time curve than that in vehicle‐treated rats. Morphine concentrations in plasma and brain were significantly increased by quinidine. The area under the plasma concentration–time curve after oral or intravenous administration of morphine was increased 5.2‐ and 1.7‐fold, respectively, in quinidine‐pretreated rats compared with vehicle‐pretreated rats. Quinidine caused a 40% decrease in the total clearance of morphine and increased the concentration of morphine in the brain, although the brain‐to‐plasma concentration ratio was not changed. Conclusions Oral administration of quinidine increases the absorption of morphine from the gastrointestinal tract and subsequently enhances the concentration in the brain and its antinociceptive effect. Enhanced intestinal absorption of morphine may be due largely to inhibition of intestinal P‐glycoprotein by quinidine.     

A new buprenorphine analogy, thenorphine, inhibits morphine-induced behavioral sensitization in mice

AIM: To investigate effects of thenorphine, a new compound of partial agonist of μ-opioid receptor, on the loco-motor activity and the behavioral sensitization to morphine in mice. METHODS: Locomotor activity was observed after administration of thenorphine or co-administration of thenorphine and morphine in mice. Mice were induced behavioral sensitization to morphine by intraperitoneal injection of 20 mg/kg morphine once daily for 7 d. Thenorphine was co-administrated with morphine to observe the effects of thenorphine on the development, transfer and expression of morphine-induced behavioral sensitization. RESULTS: A single dose of thenorphine (0.0625, 0.25, and 1.0 mg/kg) could dose-dependently inhibit the locomotor activity in mice (P<0.05), repeated administrations of thenorphine, however, were not able to induce locomotor sensitization, but induced tolerance. Pretreatment with thenorphine 30 min prior to morphine effectively inhibited the psychomotor effect of morphine in mice (P<0.01). Co-adminis     

氯诺昔康用于术后患者自控镇痛的临床疗效和安全性

目的:评价非甾体抗炎药氯诺昔康用于妇科全子宫切除术后患者自控镇痛(PCA)的疗效及安全性。方法:60例全身麻醉下行全子宫切除术术后出现中度以上疼痛的患者随机分为氯诺昔康组和吗啡组。患者根据需要启动PCA泵(氯诺昔康0.8mg/次,吗啡1mg/次,锁定时间5min)。由疼痛缓解程度(PAR)、疼痛缓解总和(TOT-PAR)和患者24h镇痛总体效果来评价镇痛效果,同时监测血小板聚集率、肝、肾功能,并观察胃肠道反应等。结果:氯诺昔康组和吗啡组的TOTPAR和镇痛总体印象评分无显著性差异(P>0.05)。吗啡组起效早于氯诺昔康 组。氯诺昔康组的恶心呕吐的发生率明显低于吗啡组。2组血小板聚集率无显著性差异(P>0.05)。结论:氯诺昔康用于妇科全子宫切除术后PCA镇痛,其镇痛效应与吗啡相近,不良反应较少。     

下丘脑一氧化氮在电针调节吗啡戒断大鼠血清黄体生成素中的作用

目的 :检测电针是否可以促进吗啡戒断大鼠血清黄体生成素 (LH)的恢复 ,并探讨一氧化氮 (NO)在这一过程中的作用。方法 :在吗啡戒断大鼠模型上 ,进行 2Hz和 10 0Hz电针治疗后 ,用酶联免疫吸附实验 (ELISA)测定大鼠血清LH的含量 ,用免疫组织化学法观察下丘脑神经元性一氧化氮合酶 (nNOS)的表达变化。结果 :多次 10 0Hz电针刺激可以显著增高吗啡戒断大鼠血清LH水平 (P <0 0 1)。吗啡戒断状态下 ,大鼠下丘脑终板血管器官 (OVLT)至喙侧视前区 (rPOA)nNOS阳性细胞数减少 (P <0 0 1,P <0 0 5 )。 10 0Hz电针治疗一周可使nNOS阳性细胞数恢复至正常水平。结论 :多次 10 0Hz电针可促进吗啡戒断大鼠血清LH的恢复 ,增强OVLT至rPOAnNOS表达水平 ,这可能是 10 0Hz电针促进吗啡戒断大鼠血清LH恢复的机制之一。     

地高辛对吗啡戒断大鼠去甲肾上腺素能神经活动的影响

目的:探讨地高辛对吗啡戒断大鼠体内去甲肾上腺素能神经活动的影响。方法:按剂量递增法建立大鼠吗啡依赖模型,给予地高辛(0.05-0.2 mg.kg-1,ig)或等体积溶媒1 h后用纳洛酮催促戒断,参考文献方法对大鼠30 min内戒断症状进行评分。处死大鼠,分离左、右心室和下丘脑,采用酶联免疫吸附法检测去甲肾上腺素(NE)和间羟去甲肾上腺素(NMN)的含量并计算其比率(NMN/NE)。结果:地高辛剂量依赖地减弱纳洛酮催促的大鼠吗啡戒断症状(F=5.264,P<0.01),其中,0.2 mg.kg-1和0.1 mg.kg-1地高辛表现出明显的统计学差异(P<0.01,P<0.05);大剂量地高辛(0.2 mg.kg-1)能明显抑制NMN以及NMN/NE值的升高(P<0.05,P<0.05)。结论:地高辛能够缓解大鼠吗啡戒断症状,其机制可能与抑制去甲肾上腺素能神经活动有关。     

硫酸吗啡与盐酸吗啡普通片对照治疗中、重度癌痛84例

目的:评价硫酸吗啡与盐酸吗啡普通片对癌症疼痛的镇痛疗效及不良反应.方法:采用多中心随机对照试验,试验组(n=44)用硫酸吗啡,对照组(n=40)用盐酸吗啡,起始量均为10～30mg,每4～6h用1次,进行个体剂量滴定,达到无痛或基本无痛的维持量继续应用,共7d.结果:2组的疼痛完全缓解率分别为77.3%与77.5%,显著缓解率为95.5%与97.5%,总有效率为100%.结论:硫酸吗啡与盐酸吗啡片治疗中、重度癌痛均有显著疗效.     

Cross-sensitization to the excitatory effect of morphine in post-dependent rats

Time-effects of morphine, methadone, meperidine and pentazocine upon locomotor activity were investigated in naive and in post-dependent rats. Dependence was induced by daily injection of 20 mg/kg (i.p.) of morphine for 30 days. Tests were run starting from 1 month after withdrawal from morphine. Morphine produced a greater increase in activity in post-dependent than in naive rats. Marked cross-sensitization to the excitatory effect occurred with methadone but not with pentazocine. The motility pattern of meperidine was similar in naive and in post-dependent animals. The findings presented here suggest that: different mechanisms underlie the excitatory actions of opiates; the narcotic character of a drug can be detected by challenging this drug in rats previously dependent on morphine.     

Bioavailability of morphine after administration of a new bioadhesive buccal tablet

A new bioadhesive buccal morphine tablet was developed for controlled release delivery of drug and improved bioavailability compared with oral controlled release tablet. In order to characterize the pharmacokinetic properties of this bioadhesive buccal formulation, a bioavailability study was performed in 12 healthy volunteers who received: a 30 mg oral controlled release tablet (A); a 20 mg aqueous solution retained in the mouth for 10 min (B); and the 60 mg bioadhesive buccal tablet placed between the lower gum and lip for 6 h (C). The mean amount of morphine absorbed from the solution was very low, only 2 mg of the 20 mg dose. After administration of forms A and C, plasma levels exhibit typical sustained release concentration–time curves. The mean amount of drug recovered from the residual bioadhesive buccal tablet after 6 h indicated that approximately 50% of the dose was released from the bioadhesive buccal tablet. The relative bioavailability of the buccal tablet (corrected for residual unabsorbed dose) compared with the controlled-release tablet was 98% based on the morphine AUC values. Good correlations between the AUC and the C_max of the bioadhesive tablet for the drug and metabolite plotted versus the amount of morphine absorbed were found. © 1998 John Wiley & Sons, Ltd.     

A comparison of testing procedures on the discriminative morphine stimulus

The study investigated the effects of reinforcement and non-reinforcement during test sessions, and the effects of duration of generalization test sessions on the generalization of a morphine-induced discriminative stimulus. Rats were trained to discriminate 3 mg/kg morphine from saline in a two-lever drug discrimination task and were then tested for generalization of 0, 1, 2, 3, 4, and 5 mg/kg morphine with the training drug under both reinforced and non-reinforced contingencies during 4-min test periods. The percentage of drug-appropriate responses and response rates were recorded for the first 2 min and the second 2 min of each test session. A higher proportion of drug-appropriate responding occurred with an intermediate dose of morphine when reinforcement was available during test sessions. The frequency of responding was higher during the last 2 min than during the first 2 min of reinforced test sessions. The changes in response rate observed between the first 2 min and the last 2 min of the test sessions also depended on the reinforcement contingency available and the dose of morphine administered presession. The testing parameters thus altered the degree of generalization and the shape of the generalization curve of the morphine discrimination.     

可乐定对吗啡依赖小鼠催促戒断后行为的影响

目的:研究吗啡依赖小鼠在纳洛酮催促戒断时可乐定治疗对稽延性戒断症状相关行为的影响。方獉法獉:采用剂量递增法使小鼠对吗啡产生依赖;每天sc盐酸吗啡3次,共3d,剂量由50mg·kg-1逐步上升到125mg·kg-1。d4sc注射50mg·kg-1吗啡1h后,可乐定治疗组小鼠ig0.6mg·kg-1可乐定,对照组ig等体积的去离子水;sc吗啡2h后各组小鼠均ip5mg·kg-1的纳洛酮进行催促戒断,观察30min内小鼠的跳跃反应和体重变化。在催促戒断后5h和24-30h通过洞板试验、悬尾试验、十字迷宫试验和自发活动试验,观察小鼠的探究行为、抑郁样行为、焦虑行为及活动性。部分小鼠在第一次戒断后10h及次日重新给予吗啡(100-125mg·kg-1)使之再次产生依赖,在d6依d4操作进行二次戒断,但不给予可乐定治疗。结果:在催促戒断试验中,可乐定可以显著降低吗啡依赖小鼠的跳跃次数和体重减轻(P<0.01);催促戒断5h后,可乐定组小鼠在洞板试验中的探洞次数比对照组少(P<0.01);在悬尾试验中的不动时间比对照组长(P<0.01);在十字迷宫试验中进入开臂的时间和次数与对照组比较差异无显著性;在自发活动试验中,前5min自发活动计数低于对照组(P<0.01),但30min内活动量与对照组比较差异无显著性;催促戒断24-30h后,两组之间的各项行为学指标差异均无显著性;在二次戒断实验中,可乐定组小鼠跳跃次数高于对照组(P<0.05),但两组小鼠体重变化差异无显著性。结论:用于拮抗吗啡依赖小鼠急性戒断症状的可乐定对戒断后的抑郁样行为有加重趋势,对焦虑行为没有影响;可乐定上述作用的行为药理学机制可能是抑制逃脱动机。     

利鲁唑对吗啡镇痛、耐受和依赖作用的影响(英文)

目的　研究利鲁唑对阿片镇痛、耐受及躯体功能的调节。方法　采用冰醋酸扭体 ,5 5℃热板法和热辐射甩尾法观察利鲁唑对小鼠痛阈及吗啡镇痛效应的影响 ;采用小鼠急性和慢性吗啡耐受模型及小鼠吗啡依赖模型 ,观察利鲁唑对吗啡耐受和依赖的作用。结果　单独皮下注射利鲁唑 2 .5～ 10mg·kg- 1在以上 3种模型无镇痛作用 ,然而能剂量依赖性地增强吗啡镇痛效应。利鲁唑 2 .5～ 10mg·kg- 1剂量依赖性地对抗吗啡引起的急性和慢性耐受。在小鼠吗啡依赖模型中 ,利鲁唑 2 .5～ 10mg·kg- 1剂量依赖性地抑制吗啡戒断症状的产生。结论　利鲁唑自身无镇痛作用 ,但能显著增强吗啡镇痛效应 ,并能预防吗啡所引起的耐受和依赖