咪唑安定对大白鼠脊髓后角广动力范围神经元伤害性刺激反应影响的研究

目的研究咪唑安定对大白鼠脊髓腰膨大部位广动力范围神经元(WDR neuron)对伤害性刺激反应的影响。方法在脊髓表面使用不同剂量的眯唑安定(M5组5μg、M10组1μg、M：。组20μg)，用微电极记录和观察脊髓后角广动力范围神经元对伤害性刺激诱发放电频率的变化，并观察氟马西尼是否能逆转此抑制作用。结果M10、M20组咪唑安定对伤害性刺激诱发的脊髓后角广动力范围神经元放电反应有抑制作用；氟马西尼对咪唑安定抑制广动力范围神经元放电反应的作用具有拮抗效应。结论经脊髓表面使用一定剂量的咪唑安定对脊髓后角广动力范围神经元对于伤害性刺激诱发的放电反应具有抑制作用；此作用可能由脊髓内苯二氮蕈类受体介导。     

苯二氮类药物对鼠中枢杏仁核神经元电活动的影响

苯二氮 类（Ｂｅｎｚｏｄｉａｚｅｐｉｎｅｓ,ＢＺ）药物是临床普遍应用的静脉麻醉药,随着新型制剂咪唑安定及其拮抗剂氟马泽尼的推出,使其应用更为广泛,但目前对该类药物的作用机理尚未完全明了,本研究应用全细胞膜片箝技术观察ＢＺ药物对杏仁核神经元电活动的影响,为探讨其中枢作用机理提供进一步理论依据。 材料和方法 选用上海产 ＳＤ小鼠,（３０± ２）ｄ,体重（１００±１０）ｇ,雌雄不拘。断头取脑,置于氧饱和（９５％Ｏ２／５％ＣＯ２）的冰盐水（４℃）中数分钟,根据鼠脑区定位图谱对杏仁核簇神经元所在脑区修块,在振…     

氟马西尼用于开胸手术全麻后拮抗咪唑安定残余作用的临床观察

开胸手术全麻后意识的恢复是拔管的一个重要指标，使用氟马西尼拮抗咪唑安定残余作用、减少开胸术后烦躁及其他并发症的发生。本文选择2001～2002年在全麻下行开胸手术病例60例，现报告如下。     

不同浓度的咪唑安定对兔离体气管平滑肌收缩的影响

目的研究不同浓度的咪唑安定对离体气管平滑肌的舒张作用,以明确咪唑安定在10-5mol/L浓度时是否能够产生较为明显的舒张作用。方法用高浓度氯化钾、乙酰胆碱、电脉冲三种刺激因素诱发兔离体气管平滑肌收缩,并观察三种不同浓度的咪唑安定对其的影响。结果1.5×10-5mol/L的咪唑安定对三种刺激因素诱发的气管平滑肌收缩不产生明显抑制作用;1.5×10-4mol/L和3.0×10-4mol/L的咪唑安定可显著抑制上述三种刺激因素诱发的气管平滑肌收缩(P<0.05或P<0.01),普萘洛尔和中枢性苯二氮卓艹类受体阻断药氟马西尼不能拮抗咪唑安定对气管平滑肌的舒张作用。结论咪唑安定在10-5mol/L左右的浓度时对兔离体气管平滑肌收缩不能产生明显的抑制作用。     

咪唑安定对大鼠丘脑束旁核感受伤害性刺激神经元的干预反应研究

目的 研究咪唑安定对大鼠丘脑束旁核感受伤害性神经元对感受外周伤害性刺激的干预反应。方法 微电极探查束旁核神经元（n=6），对找到的每个感受伤害性刺激神经元均实施以下步骤：（1）记录基础放电（A组）。（2）记录基础的伤害性刺激的放电反应（B组）。（3）平静5min后（原则上放电恢复到刺激前水平），静脉给予咪唑安定0.2mg,2min后记录伤害性刺激下的放电反应（C组）。（4）5min后，静脉给入咪唑安定的特异性拮抗剂吗泽尼0.05mg,2min后记录伤害性刺激的放电反应（D组）。结果 A组和B组差异有显著性，符合外周伤害性刺激使中枢痛敏神经元兴奋的正常重量反应。C组与B组差异有显著性，与A组差异无显著性，提示在咪唑安定的干预下，外周的伤害性刺激不能使中枢痛敏神经元兴奋，即咪唑安定对痛觉有抑制作用。D组与C、A组有显著性差异，而与B组无显著性差异，提示氟吗泽尼拮抗了咪唑安定的抑痛作用后，使中枢痛敏神经元恢复对外周伤害性刺激的敏感性。结论 咪唑安定可以显著性的抑制大鼠丘脑束旁核感受伤害性神经元对外周伤害性刺激的兴奋反应。     

咪唑安定及氟吗泽林在麻醉中的应用

自60年代苯二氮(艹卓)类(BZ)药物应用于临床以来,迄今已有近30年的历史,多年来,由于BZ有起效慢,半衰期长,作用时间个体差异大及剂量依赖性差等缺点,使其应用受限。1979年Freger合成的咪唑安定(MZ)是一种新型的BZ受体激动剂,其作用时间短,安全,术后残余作用可被其拮抗药氟吗泽林(Flumazenil简称FZ)及时消除,因此,近年来MZ和FZ的研究受到重视,进展很快,逐渐在临床麻醉中占有一定的地位。一.咪唑安定和氟吗泽林的麻醉药理     

硬膜外阻滞下辅助用药预防内脏牵拉反应的临床观察

目的：观察不同辅助药用于硬膜外阻滞下行上腹部手术时抗内脏牵拉反应的效果。方法：择期上腹部手术病人60例，随机分为4组，行T8－10硬膜外腔穿刺注药，当阻滞平面固定及血压稳定后，分组应用氟哌啶与哌替啶、氟哌啶与芬太尼、咪唑安定与哌替啶、咪唑安定与氯胺酮及欧贝4种联合用药，观察用药后对呼吸循环的影响及抗内脏牵拉反应的效果。结果：咪唑安定与氯胺酮及欧贝合剂对呼吸循环影响小，且抗内脏牵拉反应效果与哌氯合剂相似而优于氟芬合剂。结论：咪唑安定与氯胺酮及欧贝合剂抗内脏牵拉反应效果确切，副作用小，是硬膜外阻滞下行腹部手术时的较好辅助用药。     

氟马西尼对异氟醚麻醉后清醒恢复的影响

氟马西尼是苯二氮类药物的特异性拮抗药 ,用于安定类药物的催醒已有多年历史。而且文献报道氟马西尼对常用吸入麻醉药氟烷、安氟醚、异氟醚麻醉后也有催醒作用[1 ] 。我们对此进行临床研究。资料与方法一般资料　选用 5 6例 1 7～ 4 8岁整形外科病人 ,男 1 5例 ,女 4 0例 ,ASAⅠ级 ,择期在气管插管全身麻醉下行整形外科手术。病人被随机分为三组 ,观察Ⅰ组 (n =2 1 )和对照组 (n =1 8) :手术结束前 1h停用静脉麻醉药 ,单纯吸入异氟醚、氧化亚氮加氧气到手术结束。观察Ⅱ组 (n =1 7) :手术结束前 1h停用丙泊酚、芬太尼和异氟醚 ,静脉给咪…     

氟马西尼对丙泊酚的拮抗作用

目的:探讨氟马西尼是否可以拮抗丙泊酚的麻醉残余作用,加速麻醉苏醒.方法:选择30-55岁女性患者120例,择期全麻下行腹腔镜下子宫肌瘤核出术及卵巢囊肿切除术,ASAⅠ～Ⅱ级.随机分为三组氟马西尼0.5mg组(0.5mg组)氟马西尼1mg组(1mg组)和对照组,每组40例.麻醉诱导咪唑安定0.05mg/kg阿曲库胺0.5mg/kg瑞芬太尼0.4ng/kg丙泊酚3.5-5.5μg/kg血浆靶控并行气管插管,术中以丙泊酚与瑞芬太尼血浆靶控间断静推阿曲库胺维持,术毕拔管分别给予生理盐水,氟马西尼0.5mg,氟马西尼1mg,观察病人的苏醒情况.结果:0.5mg组与1mg组与对照组比较差异有显著性( p＜0.05) 0.5mg组与1mg组比较差异无显著性(p＞0.05),1mg组3例患者出现躁动.     

经鼻注氟马西尼后的血浆浓度

苯二氮革类药(BZD)镇静药,特别是咪达唑仑通常给患儿口服后能更好地接受诊断操作和急诊室处置等,但是学步儿童如果发生镇静过度,激动不安,就需要拮抗剂。氟马西尼(flumazenil)是竞争性BZD拮抗药,可逆转BZD对中枢神经系统的抑制作用,而且可以经鼻给药。成人的氟马西尼剂量静注一般为加20μg/kg,一次极量为0.2 mg。Jones等报道氟马西尼拮抗咪达唑仑的儿童静注剂量为(24±19)μg/kg。Mali-norsky等报道经鼻给咪达唑仑其生物利用度在32％-57％之间,而氟马西尼的化学结构与咪达唑仑相似,所以推断经鼻给氟马西尼的生物利用度为50％。为了检测患儿经鼻给药后的血浆氟马西尼的浓度,所以选定氟马西尼40 μg/kg(0.4 ml·kg-1)滴鼻。     

Midazolam and ketamine inhibit glutamate release via a cloned human brain glutamate transporter

PURPOSE: In cerebral ischemia/anoxia, the glutamate transporter runs in reverse and releases glutamate into the extracellular space, causing irreversible neuronal damage. Intravenous anesthetics attenuate overall glutamate release and prevent neuronal injury during anoxia/ischemia, but their effect on the glutamate transporter is variable. METHODS: A human glial glutamate transporter (hGLT-I) cDNA was isolated by screening a human cerebral cortical library. Cloned cDNA was transfected in Chinese hamster ovary cells. The effect of the intravenous anesthetics midazolam (0.3 to 30 microM), ketamine (10 to 100 microM), thiopental (30 to 300 microM), and propofol (3 to 30 microM) on reversed uptake of L-glutamate via hGLT-I was examined by whole-cell patch-clamp. RESULTS: Midazolam at a concentration 3 microM reduced outward currents arising from reversed L-glutamate uptake via hGLT-I in a concentration-dependent manner. While, ketamine at 100 microM attenuated the same outward currents, to 53.3+/-11.4% of those seen in controls without anesthetics (P<0.05, n=5). In contrast, neither thiopental nor propofol showed effects on outward currents mediated by reversed operation of hGLT-I. CONCLUSIONS: These results suggest that midazolam and ketamine, but not thiopental and propofol, have a capacity to inhibit glutamate release via GLT- I directly.     

Synergistic interactions between midazolam and alfentanil in isolated neonatal rat spinal cord

Benzodiazepines, which may themselves have analgesic properties, display complex interactions with opioids. This study was designed to investigate the effects of midazolam on nociceptive neurotransmission in isolated neonatal rat spinal cord, and the interactions between midazolam and alfentanil. Slow ventral root potentials (sVRP) were recorded from a lumbar root of spinal cords isolated from 1-7-day-old rats and superfused at 27-28 degrees C. Midazolam (35 nmol litre-1 to 15 microgramsmol litre-1) significantly (P < 0.05) depressed sVRP area in a concentration-dependent manner. Midazolam depression was antagonized by flumazenil, bicuculline and naloxone. Midazolam and alfentanil interacted synergistically, as determined by a combination index of less than 1. Midazolam blocked the rebound hyperexcitability observed when alfentanil was reversed by naloxone. The results of the study are relevant to benzodiazepine-opioid analgesia and to the effectiveness of benzodiazepines in mitigating the development of opioid tolerance and dependence.      

咪唑安定对氯胺酮诱导的c-fos基因在大鼠后扣带回皮质区表达的影响

目的 观察咪唑安定对氯胺酮诱导的c-fos基因在大鼠后扣带回皮质区表达的影响，探讨咪唑安定预防或减轻氯胺酮所致精神症状及神经损害的机制。方法 雄性Wistar大鼠30只，随机分为生理盐水5ml组、咪唑安定15mg／kg组、氯胺酮100mg／kg组、咪唑安定15mg／kg加氯胺酮100mg／kg组、氯胺酮100mg／kg加咪唑安定15mg／kg组。咪唑安定与氯胺酮两药间隔15min给药，所用药物均由腹腔注射。各组动物于用药后2h开胸经心脏灌流脑固定，用免疫组织化学方法检测后扣带回皮质区c-fos蛋白的表达，用彩色病理图像分析系统测定c-fos阳性细胞的百分率和阳性细胞的密度。结果氯胺酮可明显诱导c-fos蛋白在大鼠后扣带回皮质区的表达；咪唑安定自身不能诱导c-fos的表达；咪唑安定预处理可显著抑制氯胺酮诱导的c-fos在这一区域的表达；先用氯胺酮后给予咪唑安定仅能部分抑制c-fos的表达。结论 咪唑安定预处理可抑制氯胺酮诱导的c-fos基因在大鼠后扣带回皮质区的表达，这可能是其预防或减轻氯胺酮所致精神症状和神经损害的机制之一。     

Dynamics of striate cortical activity in the alert macaque: I. Incidence and stimulus-dependence of gamma-band neuronal oscillations

Using single and multiunit recordings in the striate cortex of alert macaque monkeys, we find that gamma-band (20-70 Hz) oscillations in neuronal firing are a prominent feature of V1 neuronal activity. The properties of this rhythmic activity are very similar to those previously observed in the cat. Gamma-band activity is strongly dependent on visual stimulation, largely absent during spontaneous activity and, under the conditions of our experiment, not time-locked to the vertical refresh of the computer monitor (80 Hz) used to present the stimuli. In our sample, 61% of multiunit activity (MUA) and 46% of single-unit activity (SUA) was significantly oscillatory, with mean frequencies of 48+/-9 and 42+/-13 Hz, respectively. Gamma-band activity was most likely to occur when cells were activated by their optimal stimuli, but still occurred, although less often and with lower amplitude, in response to nonoptimal stimuli. The frequency of gamma-band activity also reflected stimulus properties, with drifting gratings evoking higher-frequency oscillations than stationary gratings. As in the cat, the spike trains of single cells showing gamma-band oscillations often displayed a pattern of repetitive burst firing, with intraburst firing rates of 300-800 Hz. The overall similarity of rhythmic neuronal activity in the primary visual cortex of cats and monkeys suggests that the phenomenon is not species-specific. The stimulus-dependence of the rhythmic activity is consistent with a functional role in visual perception.     

Neuronal activity in GP and Vim of parkinsonian patients and clinical changes of tremor through surgical interventions

Microrecordings were performed during pallidotomy and thalamotomy for Parkinson's disease (PD). Neuronal activity in globus pallidus (GP) was in general agreement with previous studies of human and primate models of PD. Neuronal activity, where frequency of tremor appeared to oscillate independently from peripheral input, was encountered in GPi. In contrast, neuronal activity in Vim regarding frequency of firing also correlated with tremor and was passively driven by kinesthetic stimuli with a somatotopic arrangement. Pallidal lesions based on microrecording induced relative reductions of tremor, while small Vim lesions immediately alleviated tremor. Basal ganglia pathology due to dopamine depletion could generate oscillatory neuronal activity in GPi, which may cause tremor. However, peripheral feedback to the motor cortex via Vim is also significant for tremorgenesis, because Vim may be an excitatory driving source for motor cortical neurons. Thus, a Vim lesion could reduce excitability of the motor cortical neurons and abolish tremor.     

Biochemical and electrophysiologic evidence that propofol enhances GABAergic transmission in the rat brain.

The influence of propofol, a new intravenous anesthetic agent, on brain gamma-aminobutyric acid (GABA)-ergic transmission has been investigated both in vitro and in vivo. In vitro, propofol, like benzodiazepines, 1) markedly enhanced 3H-GABA binding in cortical membrane preparations; 2) potentiated muscimol-induced stimulation of 36Cl- uptake in membrane vesicle preparations (the propofol potentiating effect was antagonized by bicuculline); and 3) inhibited 35S-TBPS binding to unwashed membrane preparations from rat cerebral cortex. Finally, propofol failed to displace 3H-flunitrazepam from its binding site, indicating that its site of action in brain is different from that of benzodiazepines. In vivo, the effect of propofol was studied using single-unit recording of the electrical activity of both nondopaminergic neurons in the pars reticulata of the substantia nigra (PR neurons) and of dopaminergic neurons in the pars compacta of the substantia nigra (DA neurons). PR neurons are known to be inhibited by GABA-mimetic drugs and benzodiazepines, whereas DA neurons are tonically inhibited by PR neurons. The intravenous administration of propofol, in a fat emulsion formulation, produced a brief dose-dependent inhibition of the firing rate of PR neurons. The dose producing 50% inhibition of the firing rate was calculated to be 1.2 +/- 0.1 mg/kg. The inhibitory effect lasted less than 5 min. Repeated injections of propofol reproduced the same inhibitory response, whereas continuous infusion (0.5 mg.kg-1.min-1) produced a persistent inhibition of neuronal firing. The inhibitory effect of propofol on PR neurons was potentiated by diazepam and reversed by picrotoxin and bicuculline but was not influenced by the benzodiazepine antagonist Ro 15-1788. These findings suggest that propofol exerts a GABA-mimetic action on PR neurons by acting on a site distinct from the benzodiazepine recognition site. Unlike benzodiazepines, propofol inhibited the firing rate of DA neurons with a potency proportional to its inhibitory effect on PR neurons. The inhibition of DA neurons was reversed by bicuculline and picrotoxin. The results suggest that propofol enhances the inhibitory control over DA neurons by strionigral GABAergic neurons.     

A neuronal mechanism of propofol-induced central respiratory depression in newborn rats

The neural mechanisms of propofol-induced central respiratory depression remain poorly understood. In the present study, we studied these mechanisms and the involvement of gamma-aminobutyric acid (GABA)A receptors in propofol-induced central respiratory depression. The brainstem and the cervical spinal cord of 1- to 4-day-old rats were isolated, and preparations were maintained in vitro with oxygenated artificial cerebrospinal fluid. Rhythmic inspiratory burst activity was recorded from the C4 spinal ventral root. The activity of respiratory neurons in the ventrolateral medulla was recorded using a perforated patch-clamp technique. We found that bath-applied propofol decreased C4 inspiratory burst rate, which could be reversed by the administration of a GABAA antagonist, bicuculline. Propofol caused resting membrane potentials to hyperpolarize and suppressed the firing of action potentials in preinspiratory and expiratory neurons. In contrast, propofol had little effect on resting membrane potentials and action potential firing in inspiratory neurons. Our findings suggest that the depressive effects of propofol are, at least in part, mediated by the agonistic action of propofol on GABAA receptors. It is likely that the GABAA receptor-mediated hyperpolarization of preinspiratory neurons serves as the neuronal basis of propofol-induced respiratory depression in the newborn rat.     

Small physiologic changes in calcium and magnesium alter excitability and burst firing of CA1 pyramidal cells in rat hippocampal slices

The effects of small physiologic changes in Ca and Mg concentrations on neuronal burst firing were examined. Intracellular electrophysiologic recordings were made from CA1 pyramidal neurons in rat hippocampal slices. There was no difference in the resting potential or the input resistance of neurons bathed in the lower Ca-Mg artificial Cerebrospinal fluid (aCSF) (1.4 mM Ca; 1.3 mM Mg) compared with the higher Ca-Mg aCSF (2 mM Ca; 2 mM Mg). However, neurons in the lower Ca-Mg aCSF, but not the higher Ca-Mg aCSF, demonstrated depolarizing waves and bursts of action potentials; no single component of the aCSF accounted for this difference. Reducing the Ca from 2 to 1 mM in the higher Ca-Mg aCSF increased the mean frequency of action potentials from 28 to 171 Hz; the addition of 6-cyano-7-nitroquinoxaline-2,3-dione did not reduce the frequency. The threshold of potassium for inducing bursts was 5.25 with 1 mM Ca, 7.25 with 2 mM Ca, and 11.25 with 3 mM Ca. When Mg was reduced from 2 to 1 mM, the number of potassium-induced bursts increased to 190%; increasing Mg from 2 to 3 mM reduced the bursts to 58% (frequency with 2 mM Mg set to 100%). Small decreases in extracellular Ca and/or Mg led to increased excitability and burst firing, which may alter physiologic and pathophysiologic processes such as enhancing long-term potentiation, pain transmission, epileptogenesis, and neuronal damage and decreasing anesthetic potency. Increases in extracellular Ca and/or Mg would have the opposite effect on these processes. These effects of extracellular divalent ions on burst firing may explain some of the pathophysiologic effects of hypocalcemia and hypomagnesemia.     

Failure of single-unit neuronal activity to differentiate globus pallidus internus and externus in Parkinson disease

OBJECT: The authors examine the validity of single-unit neuronal recordings as a method of differentiating the globus pallidus internus (GPi) from the GP externus (GPe) in Parkinson Disease. METHODS: One hundred twenty-eight recordings of apparent single-unit activity used to help guide final electrode placement in eight patients who underwent pallidotomy were analyzed using sophisticated spike sorting methods, and 185 neurons were characterized for mean firing frequency and percent of firing within bursts. In addition, the total spectral power was calculated on the full measured waveform for each of 128 samples without spike sorting. No correlation was identified between these measures of neuronal activity and depth within the GP. CONCLUSIONS: These results call into question the validity of relying on single-unit activity and microelectrode recordings in the operating room to localize lesion or electrode placement within the GPi during stereotactic pallidal surgery.     

Toxicity of intravenous anaesthetics

Intravenous anaesthetic agents are generally remarkably safe. However, it is clear that propofol infusion syndrome is a real, albeit rare, entity. This often lethal syndrome of metabolic acidosis, acute cardiomyopathy and skeletal myopathy is strongly associated with infusions of propofol at rates of 5 mg/kg/hour and greater for more than 48 hours. There is evidence to support the hypothesis that the syndrome is caused by the failure of free fatty acid metabolism due to inhibition of free fatty acid entry into the mitochondria and also specific sites in the mitochondrial respiratory chain. The syndrome therefore mimics the mitochondrial myopathies. Midazolam causes seizure-like activity in very-low-birthweight premature infants requiring the drug prior to tracheal intubation or during prolonged positive pressure ventilation. This can be successfully reversed with the specific benzodiazepine antagonist flumazenil. Midazolam can also cause paradoxical reactions, including increased agitation, poor co-operation and aggressive or violent behaviour, which has been successfully managed with flumazenil.