Benzodiazepine ligands,nociception and ‘defeat’ analgesia in male mice

Recent studies have indicated that defeat experience induces acute non-opioid analgesia in intruder mice. To investigate the potential involvement of benzodiazepine receptors in this biologically-relevant form of environmentally-induced antinociception, we initially assessed the effects of some benzodiazepine ligands on basal nociception (tail-flick assay). Chlordiazepoxide (5–30 mg/kg), midazolam (0.625–5 mg/kg), diazepam (0.5–4 mg/kg), Ro15-1788 (5–80 mg/kg) and CGS8216 (5 mg/kg) were found to be ineffective in altering basal nociception. However, higher doses of CGS8216 (10–20 mg/kg) induced significant analgesia, an effect also observed with the -carboline derivatives FG7142 (5–20 mg/kg) and DMCM (1–2 mg/kg). Time-course analyses revealed that the onset of CGS8216 analgesia was slower than for FG7142 and DMCM, but that all three drugs produced long-lasting elevations in tailflick latencies. The analgesic effects of FG7142 and DMCM were completely reversed by Ro15-1788 (20 mg/kg) and by chlordiazepoxide (20 mg/kg), suggesting mediation by benzodiazepine receptor mechanisms. Although CGS8216 analgesia was also reversed by Ro15-1788, it was unaffected by chlordiazepoxide; however, diazepam (5 mg/kg) did significantly attenuate the reaction. Further studies indicated that the antinociceptive consequences of defeat experience were dose-dependently blocked by Ro15-1788 (10–40 mg/kg) and by diazepam (0.5–2 mg/kg). Surprisingly, however, neither chlordiazepoxide (5–20 mg/kg) nor midazolam (1.25–2.5 mg/kg) blocked defeat analgesia under present test conditions. Although several issues remain unresolved, present findings would not be inconsistent with the proposal that stimuli associated with the acute stress of defeat experience release an endogenous ligand which acts in an inverse agonist-like manner at benzodiazepine sites.     

咪达唑仑对剖宫产术初产妇情绪和记忆的影响

目的 探讨咪达唑仑对剖宫产手术产妇情绪和记忆的影响.方法 72例择期剖宫产术产妇随机分成4组,Ⅰ、Ⅱ和Ⅲ组麻醉前30 min分别肌注咪达唑仑0.05、0.06和0.07 mg/kg,Ⅳ组肌注生理盐水1.5 ml,同时肌肉注射阿托品0.01 mg/kg.于注药前和注药后30 min进行焦虑视觉类比试验(AVAT)、状态焦虑问卷(SAI)测试及Ramsay镇静水平评估.将麻醉准备到手术结束过程分为5阶段,每项告知产妇,记录剖宫产术后4 h产妇能准确回忆的项目.结果 注药后30 min时,Ⅰ～Ⅲ组AVAT分别下降36.4%、43.2%和43.1%;SAI分别下降20.9%、24.8%和26.9%,均获得Ramsay 2～4级镇静水平.Ⅰ～Ⅲ组和Ⅳ组比较记忆保留组间差异均有统计学意义(P均＜0.01).Ⅰ～Ⅲ组以遗忘静脉穿刺过程的居多,4组产妇对椎管内麻醉穿刺和新生儿娩出后性别识别两过程全部记忆完觋整.结论 剖宫产手术前给予咪达唑仑0.05～0.07 mg/kg,对产妇有良好的镇静和抗焦虑作用,对外显记忆有一定程度的影响,其中对信息量小和关注程度低的信息能产生顺行性遗忘作用,能保留信息量大和关注程度高的信息的完整记忆.     

Defensive reactions are counteracted by midazolam and muscimol and elicited by activation of glutamate receptors in the inferior colliculus of rats

 The inferior colliculus is involved in conveying auditory information of an aversive nature to higher cortical structures. Gradual increases in the electrical stimulation of this structure produce progressive aversive responses from vigilance, through freezing, until escape. Recently, we have shown that microinjections of NMDA into the inferior colliculus mimic these aversive effects and that the neural substrates responsible for learned escape behavior in the inferior colliculus are regulated by GABA−benzodiazepine mechanisms. In the present study, we extend these observations showing that unlearned aversive responses are also depressed by muscimol and midazolam, both GABA-benzodiazepine agonists, and that microinjection of glutamate, an excitatory amino acid, into the inferior colliculus can trigger freezing responses. Electrical stimulation of the inferior colliculus of rats placed inside an open field allowed the determination of thresholds for the aversive responses, alertness, freezing and escape. Systemic administration (3 and 5.6 mg/kg) as well as microinjections into the inferior colliculus of the anxiolytic compound midazolam (10, 20 and 40 nmol) caused increases in threshold for these aversive responses. Similar results were obtained following microinjections of the GABA-A agonist muscimol (0.1, 1 and 5 nmol) into this brainstem structure. Microinjections of low doses of glutamate (5 nmol), presumed to activate mainly AMPA/kainate receptors, into the ventrolateral division of the central nucleus of the inferior colliculus of rats placed inside a circular arena induced aversive reactions, characterized by freezing responses. However, higher doses of glutamate caused no apparent effects. GDEE, an AMPA/kainate receptor antagonist, inhibited, whereas AP7, a NMDA receptor antagonist, did not influence these responses. It is suggested that GABA-benzodiazepine processes modulate the expression of defensive reactions in the inferior colliculus and that activation of fast-acting excitatory amino acid receptors in this midbrain region can trigger the initial steps of the defense reaction without eliciting the motor explosive behavior usually seen following the activation of NMDA receptors. Received: 13 May 1998 / Final version: 12 August 1998     

Lack of accumulation of midazolam in plasma and lipoprotein fractions during intravenous lipid infusions in patients on artificial respiration

Summary Severely ill patients often require total parenteral nutrition including intravenous liqid emulsions concurrently administered with lipophilic drugs. Therefore we investigated whether therapeutic application of a mixed medium chain/long chain triglyceride infusion affects the disposition of midazolam necessary for sedation in patients on artificial respiration. The concentrations of midazolam were measured in unfractionated plasma, and in lipoprotein fractions isolated from ex vivo blood samples, including determination of triglycerides and cholesterol; the albumin level was also analysed.Midazolam in the VLDL fraction was only 0.246 g·ml^–1, whereas the total plasma concentration averaged 1.101 g·ml^–1, and the midazolam content of the LDL plus HDL fractions amounted to 1.771 g·ml^–1. Albumin in these lipoprotein fractions was just as unequally distributed. A lipid infusion resulted in a significant elevation of total triglycerides from 157 to 221 mg·dl^–1 and VLDL-triglycerides from 77 to 155 mg·dl^–1. The triglyceride content of the LDL plus HDL fraction rose from 102 to 139 mg·dl^–1. At the same time the midazolam concentration in unfractionated plasma and in the VLDL and the LDL + HDL fractions decreased to 0.899 g·ml^–1, 0.130 g·ml^–1, and 1.265 g·ml^–1, respectively. Cholesterol and albumin concentrations were not affected.The data show for the first time that a significant increase in plasma triglycerides during an intravenous lipid infusion does not result in accumulation of midazolam in lipoproteins, probably because albumin binding of the drug is very strong. The lack of midazolam trapping is important with respect to the safety of concurrent use of lipophilic drugs and intravenous lipid infusions.     

Clinical experience with continuous intravenous sedation using midazolam and fentanyl in the paediatric intensive care unit

Twenty-four patients in a paediatric intensive care unit mostly undergoing cardiac surgery, received a midazolam dosage between 50–400 g/kg per hour as a continuous intravenous infusion partly in combination with fentanyl [0,5–2,5 g/kg per hour] for analgesia and sedation. The mean duration of midazolam infusion was 11.6 days (range 38h–40 days). Blood samples for the HPLC assay of serum midazolam concentration were taken and the clearance estimated. The efficiency of sedation in correlation to the midazolam concentration was evaluated by a clinical sedation score. Serum midazolam concentrations between 100–400 g/l were sufficient for sedation. Dosage had to be increased during therapy according to an increased midazolam clearance. The evaluation of the sedation score showed that sedation of artifically ventilated infants and young children can be established by continuous intravenous infusion of midazolam.Dedicated to the 65th birthday of Prof.Dr. Erich Gladtke     

不同静脉和吸入麻醉药对罗库溴铵肌肉松弛作用的影响

目的：研究不同静脉和吸入麻醉药对罗库溴铵肌肉松弛作用的影响。方法：５０例病人分为５组，观察并比较了静脉麻醉药咪唑安定、异丙酚和吸入麻醉药（１．２ＭＡＣ）安氟醚、异氟醚和七氟醚对罗库溴铵肌肉松弛作用的影响，以及罗库溴铵对血流动力学的影响。结果：肌松作用起效时间５组间无显著差异，平均为４４．５～４９．１秒。其临床维持时间、７５％恢复时间和恢复指数三种吸入麻醉药组均显著长于两种静脉麻醉药组（Ｐ＜０．０１），而三种吸入麻醉药组间和两种静脉麻醉药组间则无显著差异。咪唑安定组和异丙酚组的肌松作用临床维持时间平均为３６．２～４１．５分钟。罗库溴铵静脉给药后血压、心率维持平稳。结论：罗库溴铵具有起效快、中等作用维持时间和血流动力学稳定的特点，但与高浓度吸入麻醉药合用可使其作用时间明显延长。     

The hedonic impact and intake of food are increased by midazolam microinjection in the parabrachial nucleus

Benzodiazepines have been reported to induce eating when administered into the brainstem of rats (either the fourth ventricle or the parabrachial nucleus). Benzodiazepines in the brainstem also have been reported to enhance the hedonic impact of taste, as measured by hedonic/aversive taste reactivity patterns, when administered to the fourth ventricle. The present study examined whether the parabrachial nucleus in particular is a brainstem site of the benzodiazepine-produced enhancement of eating and palatability. Food intake (cereal mash) was measured after brainstem microinjections of midazolam or vehicle (0.0, 7.5, and 15.0 microg) into the parabrachial nucleus, the nucleus of the solitary tract, the pedunculopontine tegmental nucleus, or the fourth ventricle (60 microg). We used the taste reactivity paradigm to measure hedonic/aversive affective reactions elicited from rats by oral infusions of a bittersweet solution (7% sucrose-0.01% quinine). Positive hedonic reactions and negative aversive reactions to sucrose-quinine were also measured after microinjections of midazolam (0.0, 7.5, and 15 microg) into the parabrachial nucleus. Midazolam increased food intake and selectively enhanced positive hedonic taste reactivity patterns to the bittersweet solution when microinjections were delivered to the parabrachial nucleus. When administered to the other brainstem sites at the same doses, however, midazolam had no effect. We therefore conclude that the parabrachial nucleus can mediate the benzodiazepine-induced enhancement of the hedonic impact of taste as well as mediating the enhancement of eating behavior.     

咪唑安定复合芬太尼在硬膜外麻醉中的应用

目的探讨咪唑安定(力月西,Midazolam)与芬太尼(Fentanyl)联合在硬膜外麻醉中的镇静程度、遗忘及抑制内脏牵拉反应的作用。方法将择期腹部手术行硬膜外麻醉患者60例,随机分为2组(Ⅰ,Ⅱ组)各30例,Ⅰ组静注咪唑安定(力月西)0.04 mg/kg,2 min后静注芬太尼0.75μg/kg;Ⅱ组静注氟哌定0.05 mg/kg 芬太尼0.75μg/kg。两组术中酌情追加首次剂量的1/3~1/2。注药后不同时段记录镇静情况,以改良警觉/镇静观察评分法(OAA/S),观察HR、SBP、DBP和SPO2及术中牵拉反应情况。结果两组在术中的镇静效果无差异,术毕Ⅰ组较Ⅱ组苏醒快,能产生较深的遗忘作用,且能更好的抑制内脏牵拉反应。结论只要加强术中管理,咪唑安定(力月西)复合芬太尼在硬膜外麻醉中能够替代芬氟合剂。     

咪达唑仑治疗儿童癫痫持续状态及惊厥频繁发作的临床研究

目的研究咪达唑仑持续静脉滴注治疗癫痫持续状态[SE,包括难治性癫痫(R SE)]及频繁惊厥发作(FCS)的临床疗效,同时探讨其安全有效剂量及副作用。方法选取收入院的SE及FCS患儿205例为观察对象,随机分为两组,治疗组103例,给予咪达唑仑持续静脉滴注;对照组102例,应用传统的一线抗癫痫药(AED s)治疗。同时将两组疗效进行对照研究,观察治疗组的最大、最小用药剂量,副反应,51例患儿进行脑电图监测。结果治疗组疗效明显高于对照组(P<0.01),治疗组的咪达唑仑安全有效剂量为1￣8μg.kg-1.m in-1,在治疗剂量下未见明显副作用,37例痫样放电随着临床发作的终止消失,14例随着发作次数的减少而减少。结论持续静脉滴注咪达唑仑治疗SE及FCS安全、可靠、有效,且常规一线AEDs治疗无效后该药仍有效,故该药可推荐为治疗癫痫持续状态及频繁惊厥发作的最佳选择。