NMDA受体和NOS参与骨癌痛小鼠吗啡耐受的形成

目的：制备骨癌痛模型,并在骨癌痛模型上模拟慢性吗啡耐受的产生,以探讨癌痛吗啡耐受的表现及机制。方法：选用40只成年雄性C57BL/6小鼠,其中20只接种Lewis肺癌细胞2×106个建立骨癌痛模型,于接种后的第15天将骨癌痛组再随机分为模型吗啡组与模型盐水组。另外20只正常小鼠完全随机分为正常吗啡组与正常盐水组。模型吗啡组和正常吗啡组小鼠皮下注射吗啡10 mg/kg,每天2次, 连续7 d, 建立慢性吗啡耐受模型,模型盐水组和正常盐水组按体质量给予等体积生理盐水。从给药的第1天开始,隔天上午给药后1 h采用机械触痛法测量小鼠的50%缩足反应阈值,以此机械触痛阈值作为疼痛指标。第7天处死小鼠分别作脊髓NMDA受体亚单位1型(NMDAR1)免疫组织化学检测和脊髓一氧化氮合酶（NOS）的定量测定。 结果：第1,3,5,7天给药后1 h行为学测试结果发现,模型盐水组和正常盐水组小鼠整个过程中50%缩足反应阈值没有明显变化。模型吗啡组第1,3,5天50%缩足反应阈值与模型盐水组相比,差异有统计学意义(P＜0.05);模型吗啡组第5天的50%缩足反应阈值与第1, 3天比较明显变小(P＜0.05);第7天模型吗啡组与模型盐水组相比,差异无统计学意义（P＞0.05）。正常吗啡组第1,3,5天50%缩足反应阈值与正常盐水组相比,差异有统计学意义(P＜0.05);第7天正常吗啡组与正常盐水组相比,差异无统计学意义（P＞0.05）。模型吗啡组的NMDAR1染色灰度值与正常吗啡组、正常盐水组及模型盐水组相比,差异有统计学意义(P＜0.05);模型盐水组的NMDAR1染色灰度值与正常盐水组相比,差异有统计学意义(P＜0.05)。模型吗啡组、模型盐水组以及正常吗啡组的积分光密度(IOD)值分别与正常盐水组相比,差异均有统计学意义(P＜0.05);模型吗啡组的IOD值与模型盐水组相比,差异有统计学意义(P＜0.05)。模型吗啡组、模型盐水组以及正常吗啡组脊髓NOS含量与正常盐水组相比,差异均有统计学意义(P＜0.05),模型吗啡组脊髓NOS含量与模型盐水组相比,差异有统计学意义(P＜0.05)。结论： 脊髓NMDA受体和NOS可能在癌痛模型吗啡耐受中起重要作用。     

Morphine reverses the effects of 1-methyl-4-phenylpyridinium in PC12 cells through activating PI3K/Akt

Aim of the study: Parkinson’s disease (PD) is a neurodegenerative disorder. It is caused by the degeneration of dopaminergic neurons and the dopamine (DA) deletion in the substantia nigra pars compacta (SNpc). Morphine elevates the level of dopamine in the mesolimbic dopamine system and plays a role in alleviating PD symptoms. However, the molecular mechanism is still unclear. The aim of the study is to investigate the mechanism on morphine alleviating PD symptoms.

Materials and methods: The viability of PC12 cells was measured by using MTT assay. The expressions of tyrosine hydroxylase (TH), thioredoxin-1 (Trx-1), CyclinD1 and Cyclin-dependent kinase5 (Cdk5) were detected by Western Blot.

Results: In present study, we found that morphine increased the cell viability in PC12 cells. 1-methyl-4-phenylpyridi-nium (MPP+) reduced the cell viability and TH expression, which were reversed by morphine. MPP+ decreased the expressions of Trx-1, CyclinD1, Cdk5, which were restored by morphine. Moreover, the role of morphine in restoring the expressions of Trx-1, CyclinD1 and Cdk5 decreased by MPP+ was abolished by LY294002, phosphatidylinositol-3-kinase (PI3K)/Akt inhibitor.

Conclusions: These results suggest that morphine reverses effects induced by MPP þ through activating PI3K/Akt pathway.     

双金解毒胶囊对吗啡依赖性动物的药效学研究

目的观察双金解毒胶囊对吗啡依赖性动物模型的脱毒药效.方法以剂量递增法造成动物对吗啡的依赖性,用纳洛酮催促戒断、自然戒断模型上,以盐酸苯氨咪唑啉作为阳性对照,评价双金解毒胶囊对吗啡依赖动物戒断症状的抑制作用.结果在吗啡依赖大鼠纳洛酮催促戒断模型,双金解毒胶囊1.6 g和3.2 g/kg,均可显著控制大鼠的戒断症状(P＜0.01),对大鼠体质量的恢复,0.8 g、1.6 g和3.2 g/kg组均较盐水对照组为快(P＜0.01).在吗啡依赖大鼠自然戒断模型,双金解毒胶囊1.6 g和3.2 g/kg组自然戒断症状显著较盐水对照组为轻(P＜0.01),体质量恢复亦较快(P＜0.01).双金解毒胶囊0.4 g、0.8 g和1.6 g/kg均可显著改善吗啡依赖猴的戒断症状(P＜0.05与0.01).结论双金解毒胶囊对吗啡依赖大鼠和猴有脱毒作用.     

吗啡依赖大鼠胰岛A细胞免疫组织化学研究

目的研究吗啡依赖大鼠Ａ细胞的变化,为探讨吗啡对Ａ细胞分泌功能的影响提供形态学依据。方法用皮下注射吗啡建立吗啡依赖大鼠模型,用免疫组织化学和图象分析方法观察胰岛Ａ细胞的变化。结果吗啡依赖大鼠Ａ细胞免疫反应增强（Ｐ＜０．０１）。结论吗啡可引起胰岛Ａ细胞分泌胰高血糖素的功能增强。     

氢吗啡酮治疗的临床应用及不良反应分析

目的：探讨氢吗啡酮治疗难治性神经病理性疼痛的疗效及不良反应分析。方法将2013年1月—2014年1月该院收治的60例难治性神经病理性疼痛患者随机分为对照组和观察组(各30例),观察组用氢吗啡酮治疗,对照组给予普瑞巴林,分析两组方案治疗4周后的疼痛缓解程度,睡眠情况并记录不良反应。结果观察组的疼痛总缓解率和明显缓解率均高于对照组(P＜0.05)。对照组和观察组治疗后的睡眠干扰评分分别为(4.2±1.3)分和(2.8±0.8)分,低于对照组(P＜0.05)。观察组不良反应少于对照组,差异有统计学意义(P＜0.05)。结论氢吗啡酮治疗难治性神经病理性疼痛的疗效较好,不良反应少,可在临床进行推广。     

罗哌卡因复合吗啡或曲马多用于术后硬膜外镇痛的观察和比较

目的　观察和比较罗哌卡因复合吗啡或曲马多用于术后硬膜外持续镇痛 (CEA)的临床效果和并发症。方法　 6 0例ASAⅠ～Ⅱ级的下腹部手术患者随机分为RM、RT 2组 ,每组 30例。手术结束时 ,RM组硬膜外注射负荷量 0 .2 %罗哌卡因 +1mg吗啡 +0 .3mg东莨菪碱共 5ml,然后接镇痛泵持续输注 0 .2 %罗哌卡因和 0 .0 0 5 %吗啡 ;RT组硬膜外注射负荷量为 0 .2 %罗哌卡因 +5 0mg曲马多 +0 .3mg东莨菪碱共 5ml,然后接镇痛泵持续输注 0 .2 %罗哌卡因和 0 .5 %曲马多 ;2组镇痛泵流速均为 2ml h ;记录使用镇痛泵后 30min及 1、4、8、2 4、4 8h各时间点VAS评分、改良Bromage分级 ,并观察恶心呕吐、尿潴留、出汗、皮肤瘙痒、呼吸抑制等并发症的发生情况。结果使用镇痛泵后各时段VAS评分、改良Bromage分级 2组间无明显差异 ,RM组恶心呕吐、尿潴留发生率明显高于RT组 (P <0 .0 5 )。结论　罗哌卡因复合吗啡或曲马多用于术后CEA均可取得良好的镇痛效果 ,而复合曲马多并发症较少 ,更为理想。     

格列苯脲可以拮抗吗啡的心肌保护作用

目的研究吗啡预处理对心肌的保护作用以及格列苯脲对其的影响。方法采用新生大鼠的原代心肌培养细胞作为研究对象,将培养心肌细胞随机分配到4组：Ⅰ组,空白对照组,共有10瓶细胞,该组细胞没有进行缺氧再复氧;Ⅱ组,缺氧再复氧组,共有10瓶细胞,该组细胞进行缺氧条件下培养6h再有氧条件下培养18h;Ⅲ组,吗啡预处理组,与Ⅱ组细胞基本相同,唯一区别是在缺氧再复氧之前,向细胞培养瓶内加入吗啡,使细胞培养瓶内培养基中含有1μmol/L浓度的吗啡,15min后,再进行缺氧再复氧。Ⅳ组,格列苯脲组,首先在缺氧再复氧之前,向细胞培养瓶内加入格列苯脲,使细胞培养瓶内培养基中含有100μmol/L浓度的格列苯脲,15min后,再向细胞培养瓶内加入吗啡,使细胞培养瓶内培养基中含有1μmol/L浓度的吗啡,15min后,再进行缺氧再复氧。最后所有细胞进行电镜检查,并且通过PI染色的流式细胞术来检测细胞凋亡情况。结果缺氧再复氧组细胞在经历6h的缺氧培养,再18h的有氧培养后,细胞大部分出现凋亡,与空白对照组细胞相比,有明显的升高（P〈0.05）,而吗啡预处理组细胞凋亡指数与缺氧再复氧组相比有明显的降低（P〈0.05）。但是格列苯脲组细胞的凋亡指数与吗啡组相比有明显升高（P〈0.05）,与缺氧再复氧组相比没有明显差别。根据电镜结果,格列苯脲组细胞与缺氧再复氧组细胞线粒体和内质网有明显的空泡变性,细胞核浓缩,而吗啡预处理组细胞形态基本正常。结论吗啡预处理可以明显抑制缺氧再复氧损伤所引起的细胞凋亡,格列苯脲可以拮抗吗啡的心肌保护作用。     

A comparison of a new analgesic,nefopam hydrochloride,with morphine sulphate,pentazocine and pethidine hydrochloride in post-operative pain

Summary

The analgesic potency of nefopam was compared to that of morphine, pentazocine and pethidine, double-blind in 200 patients with post-operative pain. Each drug was given as a single intramuscular injecton on the first post-operative day. Pain relief was measured both with a 0 to 3 graded pain scale and a 0 to 10 visual analogue scale and expressed as pain intensity, pain intensity difference and sum of pain intensity difference. The degree and time course of pain relief was similar for all four treatments with maximum analgesia 90 minutes after injection. Side-effects were reported by 58% of patients on nefopam compared to 68% on morphine, 82% on pentazocine and 74% on pethidine, the commonest side-effect being sleepiness. These results suggest that nefopam is a sufficiently potent analgesic agent to control post-operative pain, with a relatively low incidence of side-effects.     

Dose-dependent attenuation of intravenous nalbuphine on epidural morphine-induced pruritus and analgesia after cesarean delivery

Epidural morphine in patient-controlled analgesia regimens controls postoperative pain well but easily induces pruritus and other epidural morphine-related side effects. With 90 pregnant American Society of Anesthesiologists physical status II females scheduled for elective cesarean delivery, the present study was designed to evaluate the efficacy and safety profile of patient-controlled antipruritus (PCP) use of intravenous nalbuphine-based regimens for attenuation of postoperative pruritus and related side effects in combination with epidural morphine patient-controlled analgesia with regard to the quality of postoperative pain management. Patients were randomly assigned to two nalbuphine groups (5 μg/kg/hour, Group N5 or 10 μg/kg/hour, Group N10) and bolus dose of 1.6 μg/kg for PCP or the control (normal saline) group. Comparable visual analog scale scores for rest pain at each measured time interval among the three groups demonstrated that adequate pain relief was offered; however, the cumulative dose of nalbuphine administered to the patients in Group N10 attenuated the analgesic effect of epidural morphine in moving pain at POh24 only. Fewer episodes and milder severity of pruritus were observed in patients in Groups N5 and N10 at all postoperative time intervals. Epidural morphine provided good postoperative pain relief but with incommodious side effects. In addition, intravenous nalbuphine not only attenuated the incidence of pruritus but also decreased total morphine consumption. In conclusion, intravenous administration of low-dose nalbuphine (5 μg/kg/hour) for PCP maintained analgesia produced by epidural morphine and offered low pruritus incidence.     

The ALERRT® instrument: a quantitative measure of the effort required to compromise prescription opioid abuse-deterrent tablets

Background: US FDA guidance recommends measuring the degree of effort needed to manipulate abuse-deterrent (AD) opioids. The ALERRT^® instrument (PinneyAssociates; Bethesda, MD) uses visual analog scales to assess the labor, effort, and resources necessary to physically compromise AD product candidates in standardized settings. Objective: Use the ALERRT^® instrument for testing morphine abuse-deterrent, extended-release, injection-molded tablets (ADER-IMT) 60 and 100 mg and the comparators immediate-release (IR) morphine sulfate 30 mg and extended-release (ER) morphine sulfate 60 mg. Methods: Four technicians tested the products using 10 household tools. The ALERRT instrument quantified effort (all tools) and time (3 preselected tools) required for manipulation. Results: Morphine-ADER-IMT 60 and 100 mg were difficult to manipulate, as demonstrated by high scores (mean range, 71.0?99.0 and 77.0?99.5, respectively). IR and ER morphine sulfate were easy to manipulate (low scores; mean range, 2.0?14.8 and 2.3?17.5, respectively). Statistically significant mean differences between morphine-ADER-IMT and comparators’ ALERRT scores were observed. Manipulations of morphine-ADER-IMT 60 and 100 mg for 300 seconds failed to produce substantial powdering. Manipulations of IR morphine sulfate (mean range, 65.5?175.8 seconds) and ER morphine sulfate (49.3?163.0 seconds) produced substantial to complete powdering in 92% of tablets. Conclusions: Morphine-ADER-IMT was extremely difficult to manipulate versus non-AD formulations of morphine. The ALERRT system differentiated the degree of effort for manipulation of morphine-ADER-IMT and non-AD morphine formulations, indicating sensitivity of this instrument as part of Category 1 testing. By measuring the degree of effort required for manipulation, the ALERRT instrument provides an empirical assessment into the relative difficulty of manipulating opioid analgesics for abuse.