Effect of ketamine on dendritic arbor development and survival of immature GABAergic neurons in vitro.

Ketamine, a noncompetitive antagonist of the N-methyl-D-aspartate type of glutamate receptors, was reported to induce neuronal cell death when administered to produce anesthesia in young rodents and monkeys. Subanesthetic doses of ketamine, as adjuvant to postoperative sedation and pain control, are also frequently administered to young children. However, the effects of these low concentrations of ketamine on neuronal development remain unknown. The present study was designed to evaluate the effects of increasing concentrations (0.01-40 microg/ml) and durations (1-96 h) of ketamine exposure on the differentiation and survival of immature gamma-aminobutyric acidergic (GABAergic) interneurons in culture. In line with previous studies (Scallet et al., 2004), we found that a 1-h-long exposure to ketamine at concentrations > or = 10 microg/ml was sufficient to trigger cell death. At lower concentrations of ketamine, cell loss was only observed when this drug was chronically (> 48 h) present in the culture medium. Most importantly, we found that a single episode of 4-h-long treatment with 5 microg/ml ketamine induced long-term alterations in dendritic growth, including a significant (p < 0.05) reduction in total dendritic length and in the number of branching points compared to control groups. Finally, long-term exposure (> 24 h) of neurons to ketamine at concentrations as low as 0.01 microg/ml also severely impaired dendritic arbor development. These results suggest that, in addition to its dose-dependent ability to induce cell death, even very low concentrations of ketamine could interfere with dendritic arbor development of immature GABAergic neurons and thus could potentially interfere with the development neural networks.     

Drugs of Abuse, Immune Modulation, and AIDS

Illicit drugs such as amphetamines, cocaine, marijuana, and opiates alter immune function and decrease host resistance to microbes in vitro and in experimental animal models. Effects on the immune system may be mediated indirectly as a result of drug interactions in the central nervous system (CNS) or directly through activation of cognate receptors on various immune cell types. For marijuana and opioids, seven-transmembranal G protein-coupled receptors have been identified in the CNS and in the immune system that may play a functionally relevant role in immune modulation. There is accumulating evidence that sigma₁ receptors play a comparable role in cocaine-mediated alteration of immune responses. A mode by which these exogenously introduced substances affects immunity and host resistance may be by perturbing the balance of Th₁ proinflammatory versus Th₂ anti-inflammatory cytokines and lipid bioeffectors. However, while illicit drugs have been documented to alter immune functions in vitro and in animal models, there is a paucity of controlled longitudinal epidemiological studies that definitively correlate immunosuppressive effects with increased incidence of infections or immune disorders in humans, including infection with the human immunodeficiency virus (HIV) or disease progression to AIDS.     

氯胺酮对离体蟾蜍椎旁神经节细胞的抑制作用

目的　了解静脉全麻药氯胺酮对交感神经节单个神经元的作用和机制。方法　应用离体蟾蜍椎旁神经节(PVG)细胞内记录技术 ,观察不同浓度的氯胺酮对PVG细胞的膜电学特性、动作电位及兴奋性的影响。结果　对离体PVG灌流 0 .3～ 3.0mmol/L氯胺酮可浓度依赖性地引起轻度去极化反应 (n =2 0 ,P <0 .0 5 ) ,降低直接动作电位的幅度和超射值 (P <0 .0 1) ,延长半幅时程 (P <0 .0 5 ) ,并明显提高动作电位的阈电位水平 (P <0 .0 5 ) ,使刺激电流强度 放电频率关系曲线右移 ,在 3mmol/L浓度减小膜电阻 (P <0 .0 5 ) ,完全取消动作电位的产生。结论　氯胺酮对离体蟾蜍椎旁神经节细胞具有直接的抑制作用     

Intrathecal co-administration of ketamine and morphine preventing activation of astrocytes and decreasing releases of IL-1β and IL-6 from spinal cord in rats of morphine tolerance

Objective： To investigate the effects of intrathecal administration of ketamine, a non-competitive N-methy-D-aspartate receptor antagonist, combined with morphine on the activation of astrocytes and releases of IL-1β and IL-6 from spinal cord in the rats of morphine tolerance. Methods： Twenty-seven Sprague-Dawley male rats were randomly divided into sham-operated, morphine tolerance, and morphine plus ketamine group. The subarachnoid catheterication of all the rats was prepared by the method of Jianping Yang. Morphine 20μg in 10μl was adminstrated intrathecally to induce spinal morphine tolerance once daily for 5 consecutive days. Morphine and ketamine 250μg in 10μl total volume was given in morphine plus ketamine group. Three groups all received intrathecal morphine 5μg in 10μl for morphine challenge test at 24h after last administration of the morphine. After morphine challenge test, lumbar spinal tissues were taken for measurement of glial fibrillary acidic protein （GFAP） of astrocyte in lumbar spinal horn cord by immunohistochemistry and IL-1β and IL-6 of spinal cord by ELISA. Results： The decrease of %MPE induced by chronic intrathecal morphine was inhibibed by ketamine and hyperalgesia and allodynia induced by morphine-withdrawl were alleviated. The average areas, the average absorbency （A^-）, the integral absorbency （A） of GFAP immuno-reactive cells in the dorsal horn, and IL-1β and IL-6 of spinal cord were significantly larger in morphine tolerance group than in morphine plus ketamine group. Conclusion：Co-administration of ketamine and morphine enhance antinociceptive effect of morphine and prevent the development of morphine tolerance. Ketamine might attenuate the activation of astrocytes and inhibit the release of IL-1β and IL-6 from spinal cord in repeated intrathecal morphine rats.     

丙泊酚复合小剂量氯胺酮用于无痛人流的效果观察

目的比较单纯应用丙泊酚与丙泊酚复合小剂量氯胺酮应用于人工流产手术的麻醉效果。方法80例自愿终止妊娠的孕妇,随机分为P(丙泊酚组),K(丙泊酚复合氯胺酮组)两组,麻醉后观察两组病人的丙泊酚用量、入睡时间、苏醒时间、离院时间、麻醉效果及术后不良反应。结果两组病人年龄、体重、手术时间相比较无显著差异。K组丙泊酚用量(1.8±0.2mg.kg-1)明显少于P组(2.5±0.1 mg.kg-1)入睡时间两者相比较无明显差异,苏醒时间K组较P组略长,但相差时间平均1 min左右。离院时间K组也较P组略长平均相差2 min。镇痛效果观察:K组均优于P组,组间比较有显著差异。术后不良反应情况:K组术后1例出现轻微恶心呕吐,无其他不良反应。P组术后无恶心呕吐发生,但有3例下腹疼痛。结论丙泊酚复合小剂量氯胺酮用于无痛人流的麻醉效果较单纯使用丙泊酚优越。     

氯胺酮诱导的大鼠条件性位置偏爱

目的:探讨氯胺酮在大鼠模型上形成条件性位置偏爱(CPP)的特点,分析氯胺酮精神依赖性潜力。方法:(1)60只SD♂大鼠随机分为对照组、氯胺酮及吗啡阳性对照组。(2)氯胺酮组每隔24h腹腔注射氯胺酮10m·lkg-1一次,连续6d,建立大鼠氯胺酮精神依赖性模型,吗啡组给予等剂量的吗啡,对照组则给予等剂量的生理盐水;(3)氯胺酮组及吗啡组于CPP形成后给予生理盐水进行消退实验。结果:(1)氯胺酮组及吗啡组大鼠出现了明显的CPP;(2)与吗啡组相比,氯胺酮组的CPP效应更显著,但消退较快。结论:氯胺酮可诱导大鼠产生CPP,但随着时间的推移CPP消退速度较吗啡快。     

尼莫地平和氯胺酮对兔全脑缺血再灌注代谢的影响

目的 观察尼莫地平和氯胺酮对兔全脑缺血再灌注代谢的影响。方法 制作兔全脑缺血再灌注模型,随机分对照、缺血、尼莫地平和氯胺酮组。结果 各组缺血再灌注后血乳酸均高于术前(P<0.05)。缺血组和尼莫地平组再灌注后乳酸和动静脉氧压差(AVDO2)高于对照组和氯胺酮组(P<0.05)。尼莫地平有使血压降低、心率减慢的副作用。结论 缺血再灌注兔24h内乳酸堆积,AVDO2增大。氯胺酮可降低血乳酸和AV-DO2。本组剂量的尼莫地平未能改善代谢可能与其心血管抑制有关。     

阈下剂量的氯胺酮用于剖宫产术麻醉中的探讨

目的 :探讨阈下剂量氯胺酮应用于剖宫产术麻醉中的可行性。方法 :80例产妇在连续硬膜外麻醉下行剖宫产手术 ,随机分成对照组和试验组。于切皮前分别静注 0 .4m g/kg的生理盐水和氯胺酮 ,观察并记录术中低血压和阻滞不全、新生儿 Apgar评分及产妇 Sp O2 情况。结果 :试验组低血压和阻滞不全的发生率分别为 0和 5 % ,明显较对照组 30 % ,2 5 %低 ( P<0 .0 5 ) ;两组新生儿 Apgar评分及产妇 Sp O2 则无明显差异 ( P>0 .0 5 )。结论 :阈下剂量的氯胺酮应用于剖宫产术麻醉是可行的。     

咪唑安定复合氯胺酮作为基础麻醉的临床观察

目的:研究鼻腔滴入咪唑安定复合肌肉注射氯胺酮作为小儿基础麻醉的可行性。方法:30例择期小儿手术（ASAⅠ～Ⅱ级）,随机分为2组（每组15例）。Ⅰ组,肌肉注射氯胺酮6mg/kg;Ⅱ组,鼻腔滴入咪唑安定0.2mg/kg加肌肉注射氯胺酮4mg/kg。观察两组诱导效果、呼吸循环变化及其不良反应。结果:Ⅱ组与Ⅰ组相比,起效更快,术中不良反应发生率更低（P<0.01）,小儿更为合作（P<0.05）,而麻醉诱导效果无明显差异（P>0.05）。结论:鼻腔滴入咪唑安定复合肌肉泣射氯胺酮作为小儿基础麻醉要优于单纯肌肉注射氯胺酮。     

氯胺酮对老年大鼠空间学习记忆功能和海马胆碱乙酰转移酶的影响

目的:观察临床剂量的氯胺酮麻醉对老年大鼠1周和3周时空间学习记忆功能和海马胆碱乙酰转移酶(ChAT)的影响。方法:♂老年SD大鼠48只,随机分为4组(n=12)。对照1周组(C1)、氯胺酮1周组(K1)、对照3周组(C3)、氯胺酮3周组(K3)。K1、K3组腹腔首次注射氯胺酮80mg/kg,随后每隔15min追加1/2首剂量,共追加3次;C1、C3组腹腔注射等量生理盐水。处理后第1周,C1、K1组大鼠进行Morris水迷宫试验,测试各组大鼠寻找隐匿台的逃避潜伏期和空间搜索能力,每日4次,连续6d;处理后第3周,C3、K3组大鼠进行同样的测试。水迷宫测试结束后,将大鼠麻醉后灌注取脑,分别应用HE染色观察组织细胞及免疫组化方法检测ChAT阳性细胞数的改变。结果:①水迷宫结果,K1组第1~4d,大鼠寻找隐匿台的潜伏期明显长于C1组(P<0.05或0.01),但第5、6d时,二者之间无明显区别(P>0.05);对隐匿台空间位置的记忆能力K1组低于C1组(P<0.05)。K3组与C3组之间水迷宫结果比较,无明显统计学意义(P>0.05)。②免疫组化结果,K1组大鼠海马部位ChAT阳性细胞数小于C1组,差异有统计学意义(P<0.05);但K3组与C3组相比,差异无统计学意义(P>0.05)。③HE染色结果:电镜下各组大鼠海马神经元结构未见明显异常。结论:临床相关剂量的氯胺酮麻醉可导致老年大鼠短期空间学习记忆功能障碍,随时间推移,功能渐恢复,其机制可能与中枢胆碱能系统功能损害有关。