AMPA对吸入麻醉药催眠、镇痛作用的影响

目的探讨AMPA(α-amino-3-hydroxy-5-methyl-4-isox-azolepropionic acid,AMPA)对吸入麻醉药恩氟烷、异氟烷、七氟烷催眠、镇痛作用的影响。方法建立小鼠腹腔注射吸入麻醉药催眠、镇痛模型,在催眠和热板法实验中分别观察侧脑室(intracerebroventricular,icv)或鞘内(intrathecal,it)注射不同剂量的AMPA对小鼠睡眠时间(sleep time,ST)和热板法痛阈值(pain threshold in hot-plate test,HPPT)的影响。结果催眠实验中,AMPA50、75、100ng组的ST与aCSF组相比,差异无统计学意义(P>0.05)。镇痛实验中,aCSF及AMPA0.25、0.5、1.0ng it对正常对照组小鼠的HPPT均无影响(P>0.05)。AMPA0.25、0.5、1.0ng it剂量依赖性地降低吸入麻醉药镇痛小鼠的HPPT(P<0.05或P<0.01)。结论脑内的AMPA受体与吸入麻醉药恩氟烷、异氟烷、七氟烷催眠作用的关系不大,脊髓的AMPA受体参与了吸入麻醉药恩氟烷、异氟烷、七氟烷的镇痛作用。     

士的宁敏感的甘氨酸受体对吸入麻醉药催眠和镇痛作用的影响

目的探讨士的宁(strychnine,Stry)敏感的甘氨酸受体(strychnine-sensitive glycine receptor,GlyR)与吸入麻醉药异氟烷、恩氟烷、七氟烷和乙醚催眠、镇痛作用的关系。方法建立小鼠腹腔注射吸入麻醉药催眠、镇痛模型,在催醒和热板实验中分别观察侧脑室(intracerebroventricular,icv)或鞘内(intrathecal,it)注射不同剂量士的宁对小鼠睡眠时间(sleeping time,ST)和热板疼痛指数(pain index in hot-platetest,HPPI)的影响。结果催醒实验中,士的宁1、2、4μg icv对上述4种吸入麻醉药的ST均无影响(P>0.05);热板实验中,士的宁0.1、0.2、0.4μg it能够剂量依赖性地减少吸入麻醉药恩氟烷、七氟烷和乙醚镇痛小鼠的HPPI(P<0.05,P<0.01);士的宁0.1μg it对异氟烷镇痛小鼠的HPPI没有影响(P>0.05),0.2、0.4μg it可减少异氟烷镇痛小鼠的HPPI(P<0.05,P<0.01)。结论士的宁敏感的甘氨酸受体是吸入麻醉药异氟烷、恩氟烷、七氟烷和乙醚镇痛作用的重要靶位,但与其催眠作用关系不大。     

Involvement of 5-hydroxytryptamine type 3 receptors in sevoflurane-induced hypnotic and analgesic effects in mice

In the present study, we investigated the role of 5-hydroxytryptamine type 3 (5-HT(3)) receptors in hypnosis and analgesia induced by emulsified sevoflurane. A mouse model of hypnosis and analgesia was established by an intraperitoneal or subcutaneous injection of emulsified sevoflurane.We intracerebroventricularly (i.c.v.) or intrathecally (i.t.) administered YM-31636, a 5-HT(3) receptor agonist, to mice and observed sleep time during hypnosis. In addition, the tail withdrawal latency was measured using the tail withdrawal test, and the writhing time was determined using the acetic acid writhing test. In the hypnosis test, YM-31636 (5, 10 and 15 μg, i.c.v.) treatment significantly decreased emulsified sevoflurane-induced mouse sleep time (p < 0.05 or p < 0.01). YM-31636 (2.5, 5 and 10 μg, i.t.) treatment significantly and dose-dependently decreased the tail withdrawal latency (p < 0.05 or p < 0.01) and increased the writhing time (p < 0.01) of mice treated with emulsified sevoflurane. These results suggest that 5-HT(3) receptors may modulate the hypnotic and analgesic effects induced by emulsified sevoflurane.     

鞘内注射NMDA拮抗吸入麻醉药的镇痛作用

目的探讨脊髓NMDA受体与吸入麻醉药安氟醚、异氟醚、七氟醚镇痛作用的关系。方法建立小鼠注射吸入麻醉药镇痛模型,用热板法和扭体法实验分别观察鞘内注射(it)不同剂量的NMDA对其痛阈的影响。结果NMDA2.5、5、10 ng it对清醒小鼠热板法痛阈(Pain threshold in hot-p late test,HPPT)和扭体次数无明显影响(P>0.05);NMDA2.5、5、10 ng it可剂量依赖性地减少安氟醚、异氟醚、七氟醚镇痛小鼠的HPPT(P<0.05)和增加扭体反应的次数(P<0.05)。结论脊髓的NMDA受体是吸入麻醉药安氟醚、异氟醚、七氟醚镇痛作用的重要靶位。     

Strychnine-sensitive glycine receptors mediate the analgesic but not hypnotic effects of emulsified volatile anesthetics

The present study was designed to investigate the role of strychnine-sensitive glycine receptors in hypnosis and analgesia induced by emulsified volatile anesthetics. After having established the mice model of hypnosis and analgesia by intraperitoneally injecting (i.p.) appropriate doses of ether, enflurane, isoflurane or sevoflurane, we intracerebroventricularly (i.c.v.) or intrathecally (i.t.) injected different doses of strychnine and then observed the effects on the sleeping time using the awaken test and the pain index in hot-plate test (HPPI) using the hot-plate test. In the awaken test, strychnine 1, 2, 4 microg (i.c.v.) had no distinctive effect on the sleeping time of the mice treated with the four emulsified inhalation anesthetics mentioned above (p > 0.05); in the hot-plate test, strychnine 0.1, 0.2, 0.4 microg (i.t.) can significantly and dose-dependently decrease the HPPI of the mice treated with emulsified ether, enflurane and sevoflurane (p < 0.05, p < 0.01); strychnine 0.1 microg (i.t.) did not affect the HPPI of the mice treated with emulsified isoflurane (p > 0.05), but 0.2 and 0.4 microg (i.t.) can significantly decrease the HPPI of the mice treatedwith emulsified isoflurane (p < 0.05, p < 0.01). These results suggest that strychnine-sensitive glycine receptors may contribute to the analgesic but not to the hypnotic effects induced by ether, enflurane, isoflurane and sevoflurane.     

神经元烟碱受体与异氟烷、七氟烷催眠和镇痛作用的关系

目的探讨神经元烟碱受体(neuronal nicotinic acetyl-choline receptors,nnAChRs)与异氟烷、七氟烷催眠和镇痛作用的关系。方法建立小鼠催眠、镇痛模型后,在催醒、热板和扭体实验中分别观察侧脑室(intracerebroventricular,icv)或鞘内(intrathecal,it)注射不同剂量烟碱(nicotine,N)对小鼠睡眠时间(sleeping time,ST)、热板法痛阈(pain threshold in hot-plate test,HPPT)和扭体次数的影响。结果催醒实验中,烟碱10、20、40μgicv能够剂量依赖性地缩短异氟烷、七氟烷催眠小鼠的ST(P<0·05,P<0·01);热板实验中,烟碱5、10、15μgit对清醒小鼠HPPT没有影响(P>0·05),但能够剂量依赖性地减少异氟烷、七氟烷镇痛小鼠的HPPT(P<0·05,P<0·01);扭体实验中,皮下注射镇痛剂量的异氟烷、七氟烷后均能引起小鼠的扭体次数减少(P<0·01),但烟碱5、10、15μgit对异氟烷、七氟烷镇痛小鼠的扭体次数的影响差异均无显著性(P>0·05)。结论nnAChRs是异氟烷、七氟烷催眠作用的重要靶位;也是异氟烷、七氟烷抗热刺激伤害的重要靶位,但与其抗化学内脏痛作用关系不大。     

GABA的镇痛、催眠、遗忘作用及其与GABA_A受体的关系

目的探讨脑内GABA的镇痛、催眠、遗忘作用及其与GABAA受体的关系。方法小鼠侧脑室注射(intracerebrov-entricular,icv)GABA或icvGABA后,静脉注射(intravenous,iv)GABAA受体阻断药一叶秋碱(securinine,Se),分别用热板和扭体实验、催醒实验、跳台和避暗实验,观察小鼠热板疼痛指数(pain threshold index in hot-plate test,HPPI)和扭体次数(writhing times)、睡眠时间(sleeping time,ST)、跳台和避暗的潜伏期(latancy)和错误次数(number of errors)的变化。结果GABA能剂量依赖性地增大HPPI,减少扭体次数;延长ST;缩短跳台和避暗潜伏期,增加错误次数;Se能拮抗以上作用。结论GABA可产生镇痛、催眠和遗忘效应,GABAA受体是GABA上述作用的重要靶位。     

γ-羟基丁酸受体与恩氟烷、异氟烷镇痛、催眠作用的关系

目的探讨γ-羟基丁酸(gamma-hydroxybutyric acid,GHBA)受体与吸入麻醉药异氟烷和恩氟烷催眠、镇痛作用的关系。方法建立小鼠腹腔和皮下注射吸入麻醉药催眠、镇痛模型。在催醒、热板和扭体实验中分别观察侧脑室(intracerebroventricular,icv)或鞘内(intrathecal,it)注射不同剂量GHBA受体拮抗剂NCS-382对小鼠睡眠时间(sleepingtime,ST)、热板疼痛指数(pain index in hot-plate test,HPPI)和扭体次数(writhing times)的影响。结果催醒实验中,NCS-3821、5、25μg icv均可使异氟烷和恩氟烷催眠小鼠的ST缩短(P<0.01);热板实验中,NCS-3821、5、25μg it对清醒和镇痛小鼠的HPPI没有影响(P>0.05);扭体实验中,皮下注射异氟烷和恩氟烷后引起小鼠的扭体次数减少(P<0.01),但NCS-3821、5、25μg it对清醒小鼠及镇痛小鼠的扭体次数均无明显影响(P>0.05)。结论γ-羟基丁酸受体是吸入麻醉药异氟烷和恩氟烷催眠作用的靶位之一,但与其抗热刺激伤害和抗化学内脏痛作用关系不大。     

咪达唑仑对异氟烷小鼠的镇痛、催眠作用的影响

<正>异氟烷(Isoflurane,Iso)是临床常用吸入麻醉药。有研究发现[1],GHB受体、神经元烟碱受体与吸入麻醉药的催眠作用有关,而NMDA、GlyR及AMPA与其镇痛作用有关,但是GABA受体与吸入麻醉药的镇痛作用的关系还不明确[2]。咪达唑仑(Midazolam,Mid)是一种含咪唑环的苯二氮     

麻醉气体吸附器在异氟醚吸入全麻中的应用

目的　评估使用麻气体吸附对异氟醚吸入全麻的病人苏醒和对手术室污染状况的影响。方法　 30例病人 ,ASAⅠ -Ⅱ拟行异氟醚吸入麻醉。麻醉气体的吸附器安装在回路中 ,在苏醒阶段将活瓣打开 ,同时记录苏醒时间、血流动力学和血气分析各项指标。以上病人例在麻醉进行当中 ,废气排气口接废气吸收器 ,同时记录吸附器前后麻醉气体的浓度 ,计算麻醉气体的吸附率。结果　病人在清醒期苏醒时间明显缩短 ,与没有用麻醉吸附器相比 ,麻醉吸附器可以明显降低排入手术室麻醉气体的浓度。使用过程中 ,各项血流动力学指标和血气分析指标均正常。结论　麻醉气体吸附器的使用可以明显提高手术室的空气质量 ,同时在麻醉恢复期。病人的苏醒时间明显缩短而且安全可靠。     

昂丹司琼对异氟烷催眠和镇痛作用的影响

目的观察昂丹司琼对异氟烷催眠和镇痛作用的影响;探讨异氟烷的催眠、镇痛作用与5-羟色胺3受体(5-HT3)的关系。方法①催醒实验小鼠ip给予昂丹司琼1,2,4 mg·kg-1,15 min后ip给予异氟烷1.0 ml.kg-1催眠,检测翻正反射消失时间。②催眠半数有效量ED50测定小鼠ip给予昂丹司琼2 mg·kg-1,15 min后用序贯法ip给予异氟烷1.12,0.90,0.72,0.58和0.46 ml.kg-1,测定催眠ED50。③扭体法小鼠ip给予昂丹司琼1,2和4 mg·kg-1,10 min后sc给予异氟烷1.0 ml.kg-1镇痛,检测扭体次数。④热板法小鼠ip给予昂丹司琼1,2和4 mg·kg-1,10 min后,ip给予异氟烷0.4 ml.kg-1镇痛,检测小鼠热板法痛阈值(HPPT)。结果与正常对照组相比,昂丹司琼1,2和4 mg·kg-1组小鼠翻正反射消失持续的时间和ED50值均无明显变化。扭体实验中,与正常对照组比较,昂丹司琼4 mg·kg-1和异氟烷1.0 ml.kg-1可使清醒小鼠扭体次数减少(P<0.01),麻醉小鼠给予昂丹司琼1,2和4 mg·kg-1时,扭体次数有下降趋势,但无统计学差异。热板法中,ip昂丹司琼对清醒小鼠及异氟烷小鼠的HPPT均无明显影响。结论昂丹司琼对异氟烷催眠、抗热刺激伤害作用无明显影响,提示异氟烷的催眠镇痛作用可能与5-HT3受体无明显关系。     

Spinal alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors may mediate the analgesic effects of emulsified halogenated anaesthetics

1. The present study was designed to investigate the relationship between spinal cord alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and the analgesic effects of emulsified halogenated anaesthetics. 2. After having established the mouse model of analgesia by intraperitoneal or subcutaneous injections of appropriate doses of emulsified enflurane, isoflurane or sevoflurane, we injected different doses of AMPA intrathecally and observed effects on the pain threshold using the hot-plate and acetic acid-induced writhing tests. 3. The results showed that intrathecal injection of AMPA (0.25, 0.5 and 1.0 ng) did not affect the pain threshold on the hot-plate test or the writhing times in conscious mice. In contrast, AMPA (0.25, 0.5 and 1.0 ng intrathecally) significantly and dose-dependently decreased the pain threshold on the hot-plate test and increased the writhing times in mice treated with emulsified anaesthetics. 4. These results suggest that spinal AMPA receptors may be important targets for the analgesic effects of emulsified enflurane, isoflurane and sevoflurane.     

The discovery of new anesthetics by targeting GABAA receptors

Introduction: Many of the general anesthetics, currently used in clinical practice, work through interactions with GABA_A receptors. The last 2 decades has witnessed substantial progress in defining the molecular mechanisms by which general anesthetics interact with GABA_A receptor sites. However, despite progress in the basic scientific understanding of the mechanism of action of general anesthetics, introduction of novel general anesthetic agents into clinical practice has proven quite challenging.

Areas covered: The focus of this review is on the potential for translating basic science advances into the design of new and improved anesthetics. The authors review general anesthetics in current practice as well as anesthetic drug candidates in development and discuss the potential for novel anesthetic drug development.

Expert opinion: Opportunities for the discovery of new anesthetics include: computational-based ligand-design, structure-based design, re-exploration of old structure–activity data, absorption, distribution, metabolism, excretion and toxicity predictions and high-throughput screening. The authors believe a lack of high-resolution three-dimensional structures of mammalian GABA_A receptors remains a significant limiting factor in structure-based anesthetic drug design.     

侧脑室或鞘内注射烟碱对恩氟烷催眠和镇痛作用的影响

目的初步分析恩氟烷的催眠和镇痛作用与神经元烟碱受体之间的关系。方法催醒实验:小鼠ip恩氟烷2.2mL.kg-1,翻正反射消失1min后,分别脑室注射烟碱10,20和40μg(5μL),记录翻正反射恢复时间(即睡眠时间)。镇痛实验:①甲醛实验:小鼠ip恩氟烷0.5mL.kg-1,5min后分别鞘内注射烟碱5,10和15μg(5μL),再5min后于足底皮下注射2%甲醛溶液20μL,记录60min内小鼠舔被注射足的累积时间。②热板实验:给药方法同甲醛实验,于注射烟碱后5,10,15,20和25min记录小鼠足部接触热板至开始添后足的时间作为后足痛阈。结果脑室注射烟碱能明显减少恩氟烷催眠小鼠的睡眠时间;鞘内注射烟碱不能拮抗甲醛实验中恩氟烷的镇痛作用,但可拮抗热板实验中恩氟烷的镇痛作用。结论神经元烟碱受体可能是恩氟烷催眠作用的重要靶位之一;也可能是恩氟烷对热刺激镇痛作用的重要靶位之一,而非对化学、炎性刺激镇痛作用的靶位。     

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors participate in the analgesic but not hypnotic effects of emulsified halogenated anaesthetics

The present study was designed to investigate the role of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in hypnosis and analgesia induced by emulsified inhalation anaesthetics. After having established the mice model of hypnosis and analgesia by intraperitoneally injecting appropriate doses of emulsified enflurane, isoflurane or sevoflurane, we intracerebroventricularly or intrathecally injected different doses of AMPA and then observed the effects on the sleep time using hypnosis test and the tail-withdrawal latency using the tail-withdrawal test. In hypnosis test, AMPA (50, 75 and 100 ng, intracerebroventricularly) had no distinctive effects on the sleep time of the mice treated with emulsified inhalation anaesthetics (P > 0.05). In tail-withdrawal test, AMPA (0.25, 0.5 and 1.0 ng, intrathecally) significantly and dose-dependently decreased the tail-withdrawal latency (P < 0.05 or P < 0.01) in the mice treated with emulsified anaesthetics. These results suggest that AMPA receptors may participate in the analgesic but not in the hypnotic effects induced by emulsified enflurane, isoflurane or sevoflurane.     

A rapid method for evaluating the behavioral effects of phencyclidine-like dissociative anesthetics in mice

A simple and rapid method for detecting the behavioral effects of phencyclidine and related dissociative anesthetics is described. Dissociative anesthetics such as phencyclidine (PCP) and dizolcipine, which bind with high affinities at N-methyl-D-aspartate (NMDA) coupled cation channels (“PCP receptors”), produced a dose-related increase in the percentage of mice that fell from a 1.5 cm deep circular arena mounted on a 60 cm platform. A similar behavior was not manifest by other classes of compounds examined including competitive NMDA antagonists, an antagonist at strychnine-insensitive glycine receptors, and σ-receptor ligands with moderate to low affinities for PCP receptors. Pretreatment of mice with glycine reduced in a dose-dependent manner the percentage of falls elicited by a maximally effective dose of dizolcipine. This simple procedure may prove useful for both the rapid detection of dissociative anesthetics and evaluation of putative PCP antagonists.     

Spinal N-methyl-D-aspartate receptors may mediate the analgesic effects of emulsified halogenated anesthetics

The present study was designed to investigate the relationship between spinal cord N-methyl-D-aspartate (NMDA) receptors and the analgesic effects of emulsified halogenated anesthetics. After having established the mouse model of analgesia by intraperitoneally or subcutaneously injecting appropriate doses of emulsified enflurane, isoflurane or sevoflurane, we intrathecally injected different doses of NMDA and then observed the effects on the pain threshold using the hot-plate test and the acetic acid-induced writhing test. The results showed that intrathecal injection of NMDA (2.5, 5 and 10 ng) did not affect the pain threshold on the hot-plate test or the writhing times in conscious mice (p > 0.05); in contrast, NMDA (2.5, 5 and 10 ng intrathecally) can significantly and dose dependently decrease the pain threshold on the hot-plate test (p < 0.05 or p < 0.01) and increase the writhing times (p < 0.05 or p < 0.01) in the mice treated with emulsified anesthetics. These results suggest that spinal NMDA receptors may be important targets for the analgesic effects of emulsified enflurane, isoflurane and sevoflurane.     

Peripheral, but not central effects of cannabidiol derivatives: mediation by CB(1) and unidentified receptors

Delta-9 tetrahydrocannabinol (Δ⁹-THC) and (−)-cannabidiol ((−)-CBD) are major constituents of the Cannabis sativa plant with different pharmacological profiles: (Δ⁹-THC activates cannabinoid CB₁ and CB₂ receptors and induces psychoactive and peripheral effects. (−)-CBD possesses no, or very weak affinity for these receptors. We tested a series of (+)- and (−)-CBD derivatives for central and peripheral effects in mice. None of the (−)-CBD derivatives were centrally active, yet most inhibited intestinal motility. Of the five (+)-CBD derivatives, all with CB₁ receptor affinity, only (+)-7-OH-CBD-DMH (DMH=1,1-dimethylheptyl), acted centrally, while all five arrested defecation. The effects of (+)-CBD-DMH and (+)-7-OH-CBD-DMH were inhibited by the CB₁ receptor antagonist SR141716. The CB₂ receptor antagonist SR144528, and the vanilloid TRPV1 receptor antagonist capsazepine, had no influence. Further, the (−)-CBD derivatives (−)-7-COOH-CBD and (−)-7-COOH-CBD-DMH, displayed antiinflammatory activity.

We suggest that (+)-CBD analogues have mixed agonist/antagonist activity in the brain. Second, (−)-CBD analogues which are devoid of cannabinoid receptor affinity but which inhibit intestinal motility, suggest the existence of a non-CB₁, non-CB₂ receptor. Therefore, such analogues should be further developed as antidiarrheal and/or antiinflammatory drugs. We propose to study the therapeutic potential of (−)- and (+)-CBD derivatives for complex conditions such as inflammatory bowel disease and cystic fibrosis.     

Strychnine-sensitive glycine receptors mediate analgesia induced by emulsified inhalation anaesthetics in thermal nociception but not in chemical nociception

The present study was designed to investigate the role of strychnine-sensitive glycine receptors in analgesia induced by emulsified inhalation anaesthetics. After having established the mice model of analgesia by intraperitoneal or subcutaneous injections of appropriate doses of ether, enflurane, isoflurane or sevoflurane, we injected different doses of strychnine intrathecally and then observed the effects on the tail-flick latency using the tail-withdrawal test and the writhing times and acetic acid-induced writhing test. In the tail-withdrawal test, all four emulsified inhalation anaesthetics (intraperitoneally) significantly increased the tail-flick latency (P < 0.01) compared with baseline, and the increase of tail-flick latency induced by four emulsified inhalation anaesthetics can be abolished by intrathecally injected strychnine. In the acetic acid-induced writhing test, writhing times inhibition induced by subcutaneous administration of four emulsified inhalation anaesthetics was not effected by intrathecal strychnine (0.1, 0.2 and 0.4 microg). The data presented in this study suggest that glycine receptors are specifically involved in mediating the analgesic effect of ether, enflurane, isoflurane and sevoflurane on thermal-induced nociception but not chemically induced nociception.