去甲肾上腺素和多巴胺在利多卡因致大鼠惊厥过程中的作用
|
摘要
目的:应用利多卡因致大鼠惊厥模型,在儿茶酚胺合成限速酶酪氨酸羟化酶(tyrosine hydroxylase,TH)抑制剂α-甲基-ρ-酪氨酸(alpha-methyl-ρ-tyrosine,AMPT)以及去甲肾上腺素转运蛋白(Norepinephrine transporter,NET)抑制剂地昔帕明的作用下,观察TH免疫活性以及测定惊厥过程中纹状体部位细胞外液去甲肾上腺素(norepinephrine,NE)与多巴胺(dopamine, DA)含量,探讨去甲肾上腺素与多巴胺在利多卡因致大鼠惊厥过程中的作用。
方法:
1实验分组及动物模型制备
24只Wistar雄性大鼠,体重250±20 g (河北医科大学实验动物中心提供)。随机分为4组,每组6只。大鼠5%异氟烷(isoflurane)麻醉后气管插管,手术过程中持续吸入3 %异氟烷维持麻醉,右股静脉置管以1ml/h的速度输入乳酸钠林格氏液。刺入电极持续监测心电图(ECG)和脑电图(EEG)。纹状体定位(A,- 1.2 cm; M,-2.8 cm; D, 3.5 mm)、钻颅孔、划破硬膜,微透析针以此坐标点垂直刺入硬膜下脑组织。操作结束1小时脑电图波形稳定后,以2μl/min的速度注入乳酸钠林格氏液,收集脑组织微透析液20分钟,之后按照实验分组给予不同处理。L组:注射生理盐水1ml,30分钟后单次泵入2%利多卡因0.1 ml,见脑电图无异常棘波继续以4mg·kg-1·min-1速度持续泵入,直到EEG上出现振幅超过100μV宽大快速的簇状棘波并持续10秒以上,停止输入利多卡因。A+L组:在泵入利多卡因前30分钟经腹腔注射α-甲基-ρ-酪氨酸( alpha-methyl-ρ-tyrosine AMPT)溶液250mg/kg,输入利多卡因的量和速度以及停止时间均与L组相同。D+L组:在泵入利多卡因前30分钟,腹腔注射地昔帕明20mg/kg,余操作同L组。C组:与L组相比仅在泵入利多卡因时泵入相同剂量的乳酸钠林格氏液,余操作均与其相同。记录惊厥波发生及持续时间、呼吸抑制及持续时间。分别在微透析针置入60分钟及L组出现惊厥波时(其他三组于相应时间点)两个时间点采集股动脉血测动脉血氧分压(PaO2)和二氧化碳分压(PaCO2),呼吸抑制期间给予辅助呼吸,维持PaO2和PaCO2在正常范围。
2标本采集
操作结束1小时待脑电图波形稳定后(T1)收集脑微透析液20分钟,输入利多卡因后(T2)再收集20分钟。实验后,大鼠深麻醉经左心0.9%生理盐水和4%多聚甲醛溶液各50 ml灌流、固定,完整取出脑组织,浸入4%多聚甲醛溶液中保存备用。
3标本的检测方法
3.1免疫组织化学染色法
脑组织切片5μm、脱蜡,经抗原修复滴加试剂、抗体,经DAB染色在显微镜下观察显色,每个切片在高倍镜下取4个视野进行TH阳性细胞计数并计算平均值。
3.2高效液相色谱—荧光检测法测定脑微透析液NE、DA的含量
样品测定:绘制标准曲线,求得去甲肾上腺素、盐酸多巴胺的浓度与峰面积回归方程,对样品进行测定求得去甲肾上腺素、盐酸多巴胺的峰面积,检测探针回收率,按照回归方程、探针回收率及盐酸多巴胺与多巴胺的换算关系计算大鼠脑纹状体去甲肾上腺素、多巴胺的实际含量。
结果: 1各组呼吸抑制持续时间比较
C组和A+L组均无呼吸抑制;L组呼吸抑制持续时间为21.83±1.69分钟;D+L组呼吸抑制持续时间为14.67±1.37分钟。与L组比较,D+L组呼吸抑制持续时间明显减少(P<0.05)。
2各组棘波持续时间比较
C组无棘波出现,L组棘波持续时间为25.67±0.75分钟;A+L组棘波持续时间为8.33±1.13分钟;D+L组棘波持续时间为13.5±2.07分钟。
与L组比较,A+L组、D+L组棘波持续时间均减少(P<0.05);与A+L组比较,D+L组棘波持续时间延长(P<0.05)。
3 C组、L组、A+L组大鼠大脑黑质部位酪氨酸羟化酶阳性细胞数比较
C组阳性细胞数为34.83±1.47个;L组阳性细胞数为84.33±3.78个;A+L组阳性细胞数为54.00±1.55个。
与C组比较,L组阳性细胞数明显增加,A+L组阳性细胞数亦增加(P<0.05);与L组比较,A+L组阳性细胞数减少(P<0.05)。
4 C组、L组、A+L组大鼠脑细胞外液T2去甲肾上腺素、多巴胺的含量比较
C组去甲肾上腺素、多巴胺的含量分别为351.78±10.15 ng/ml,316.80±6.62 ng/ml,L组去甲肾上腺素、多巴胺的含量分别为524.61±17.85 ng/ml,758.42±15.46 ng/ml,A+L组420.68±5.79 ng/ml,483.61±6.24 ng/ml
与C组比较,L组去甲肾上腺素、多巴胺的含量均增加(P<0.05);A+L组去甲肾上腺素、多巴胺的含量均增加(P<0.05);与L组比较,A+L组去甲肾上腺素、多巴胺的含量均降低(P<0.05)。
5 TH阳性细胞数与C组、L组、A+L组棘波持续时间呈正相关,直线回归方程为Y=0.52X-18.65 R2=0.99。
6三组TH阳性细胞数与T2大鼠脑细胞外液去甲肾上腺素、多巴胺的含量呈正相关关系,直线回归方程分别为Y=3.5X+230.28 R2=1.00;Y=8.87X+7.47 R2=1.00。
7 T2大鼠脑细胞外液去甲肾上腺素、多巴胺的含量与棘波持续时间呈正相关关系,直线回归方程分别为Y=0.15X-52.33 R2=0.98;Y=0.06X-19.11 R2=0.99。
8 L组T1与T2去甲肾上腺素、多巴胺含量的比较L组T1去甲肾上腺素含量358.9±9.12ng/ml,多巴胺319.35±6.64ng/ml, T2去甲肾上腺素、多巴胺含量与T1比较明显升高(P<0.05)
9 A+L组T1与T2去甲肾上腺素、多巴胺含量的比较A+L组T1去甲肾上腺素含量357.63±10.58ng/ml,多巴胺319.83±8.58ng/ml,T2去甲肾上腺素、多巴胺含量与T1比较明显升高(P<0.05)
结论:
1利多卡因致大鼠惊厥过程中纹状体脑细胞外液NE、DA均升高,其原因可能是神经元TH免疫活性增强。
2 DA在利多卡因致大鼠惊厥过程中起着更重要的作用
3 NE对利多卡因致大鼠惊厥有抑制作用。
Objective: In order to determine the contention of NE and DA in extracellular fluid in striatum of rats with convulsion,we make a model of lidocaine-induced convulsion. TH immunoactivity and change of concentration of NE and DA are observed, AMPT and desipramine were injected to investigate different role of norepinephrine and dopamine in the process of lidocaine-induced convulsion in striatum in rats.
Methods: Twenty-four male wistar rats weighing 250±20mg were randomly divided into 4 groups(n=6 . After anesthetized by isoflurane, a rat was placed in the stereotaxic frame and a microdialysis probe was placed into the striatum (A–1.2cm, M–2.8cm, D 3.5mm, from bregma and dural surface). Microdialysis samples were collected per 20 min after EEG waves were stable. (1) group L: After saline was injected i.p, lidocaine was single pumped into femoral vein for 30 min, and pumped at a rate of 4mg·kg-1·min-1 if multiple high-voltage spikes could not be seen. (2) group C: The process was same with group L except lactated Ringer Solution was pumped into femoral vein. (3) group A+L: The process was same with group L except AMPT was pumped into femoral vein. (4) group D+L: The process was same with group L except desipramine was pumped into femoral vein. After collecting microdialysis samples,rats were perfused and fixed through cardia. Tissue sections of brain tissue were underwent antigen recovering and droping agent and DAB, TH positive immunoactive neurons were observed under high power field of optical microscope. The concentrations of extracellular norepinephrine and dopamine in striatum and the recolleting rate of microdialysis probe were detected by the method of HPLC-fluorescence, according to recolleting rate and reforming relation of dopamine hydrochloride with dopamine to calculate concentrations of NE and DA in striatum in rats.
Results:
1 Results of respiratory depression and spikes Group D+L lasting time of respiratory depression was significantly shortencompared with group L (P<0.05). Group A+L and group D+L lasting time of multiple high-voltage spikes were significantly shorten compared with group L (P<0.05 ).
2 Results of TH immunoactivity in substantia nigra
TH positive immunoactive neurons in group A+L were significantly decreased compared with group L (P<0.05). TH positive immunoactive neurons in group A+L were significantly increased compared with group C (P<0.05).
3 Concentration of NE and DA in T2
Concentrations of NE and DA in group A+L were significantly decreased compared with group L (P<0.05)., Concentrations of NE and DA in group A+L were significantly increased compared with group C (P<0.05 each). There were significant differences among them (P<0.05).
4 Relation of each index
TH positive immunoactive neurons were directly correlated with spikes lasting time, Y=0.52X-18.65 R2=0.99. TH positive immunoactive neurons were directly correlated with concentrations of NE and DA in T2, Y=3.5X+230.28 R2=1.00 Y=8.87X+7.47 R2=1.00. Spikes lasting time were directly correlated with concentrations of NE and DA in T2, Y=0.15X-52.33 R2=0.99; Y=0.06X-19.11 R2=0.99.
5 Concentrations of NE and DA in T2 compared with T1
Concentrations of NE and DA in T2 were significantly increased compared with that in T1 in group L(P<0.05). Concentrations of NE and DA in T2 were significantly increased compared with that in T1 in group A+L (P<0.05 each).
Conclusion:
1 Concentrations of NE and DA in extracellular fluid in striatum in rats were increased during lidocain-induced convulsion. The increase of NE and DA may be attribute to activation of TH .
2 DA play a importent role in convulsion induced by lidocaine.
3 NE may play a depressant role in convulsion induced by lidocaine.
方法:
1实验分组及动物模型制备
24只Wistar雄性大鼠,体重250±20 g (河北医科大学实验动物中心提供)。随机分为4组,每组6只。大鼠5%异氟烷(isoflurane)麻醉后气管插管,手术过程中持续吸入3 %异氟烷维持麻醉,右股静脉置管以1ml/h的速度输入乳酸钠林格氏液。刺入电极持续监测心电图(ECG)和脑电图(EEG)。纹状体定位(A,- 1.2 cm; M,-2.8 cm; D, 3.5 mm)、钻颅孔、划破硬膜,微透析针以此坐标点垂直刺入硬膜下脑组织。操作结束1小时脑电图波形稳定后,以2μl/min的速度注入乳酸钠林格氏液,收集脑组织微透析液20分钟,之后按照实验分组给予不同处理。L组:注射生理盐水1ml,30分钟后单次泵入2%利多卡因0.1 ml,见脑电图无异常棘波继续以4mg·kg-1·min-1速度持续泵入,直到EEG上出现振幅超过100μV宽大快速的簇状棘波并持续10秒以上,停止输入利多卡因。A+L组:在泵入利多卡因前30分钟经腹腔注射α-甲基-ρ-酪氨酸( alpha-methyl-ρ-tyrosine AMPT)溶液250mg/kg,输入利多卡因的量和速度以及停止时间均与L组相同。D+L组:在泵入利多卡因前30分钟,腹腔注射地昔帕明20mg/kg,余操作同L组。C组:与L组相比仅在泵入利多卡因时泵入相同剂量的乳酸钠林格氏液,余操作均与其相同。记录惊厥波发生及持续时间、呼吸抑制及持续时间。分别在微透析针置入60分钟及L组出现惊厥波时(其他三组于相应时间点)两个时间点采集股动脉血测动脉血氧分压(PaO2)和二氧化碳分压(PaCO2),呼吸抑制期间给予辅助呼吸,维持PaO2和PaCO2在正常范围。
2标本采集
操作结束1小时待脑电图波形稳定后(T1)收集脑微透析液20分钟,输入利多卡因后(T2)再收集20分钟。实验后,大鼠深麻醉经左心0.9%生理盐水和4%多聚甲醛溶液各50 ml灌流、固定,完整取出脑组织,浸入4%多聚甲醛溶液中保存备用。
3标本的检测方法
3.1免疫组织化学染色法
脑组织切片5μm、脱蜡,经抗原修复滴加试剂、抗体,经DAB染色在显微镜下观察显色,每个切片在高倍镜下取4个视野进行TH阳性细胞计数并计算平均值。
3.2高效液相色谱—荧光检测法测定脑微透析液NE、DA的含量
样品测定:绘制标准曲线,求得去甲肾上腺素、盐酸多巴胺的浓度与峰面积回归方程,对样品进行测定求得去甲肾上腺素、盐酸多巴胺的峰面积,检测探针回收率,按照回归方程、探针回收率及盐酸多巴胺与多巴胺的换算关系计算大鼠脑纹状体去甲肾上腺素、多巴胺的实际含量。
结果: 1各组呼吸抑制持续时间比较
C组和A+L组均无呼吸抑制;L组呼吸抑制持续时间为21.83±1.69分钟;D+L组呼吸抑制持续时间为14.67±1.37分钟。与L组比较,D+L组呼吸抑制持续时间明显减少(P<0.05)。
2各组棘波持续时间比较
C组无棘波出现,L组棘波持续时间为25.67±0.75分钟;A+L组棘波持续时间为8.33±1.13分钟;D+L组棘波持续时间为13.5±2.07分钟。
与L组比较,A+L组、D+L组棘波持续时间均减少(P<0.05);与A+L组比较,D+L组棘波持续时间延长(P<0.05)。
3 C组、L组、A+L组大鼠大脑黑质部位酪氨酸羟化酶阳性细胞数比较
C组阳性细胞数为34.83±1.47个;L组阳性细胞数为84.33±3.78个;A+L组阳性细胞数为54.00±1.55个。
与C组比较,L组阳性细胞数明显增加,A+L组阳性细胞数亦增加(P<0.05);与L组比较,A+L组阳性细胞数减少(P<0.05)。
4 C组、L组、A+L组大鼠脑细胞外液T2去甲肾上腺素、多巴胺的含量比较
C组去甲肾上腺素、多巴胺的含量分别为351.78±10.15 ng/ml,316.80±6.62 ng/ml,L组去甲肾上腺素、多巴胺的含量分别为524.61±17.85 ng/ml,758.42±15.46 ng/ml,A+L组420.68±5.79 ng/ml,483.61±6.24 ng/ml
与C组比较,L组去甲肾上腺素、多巴胺的含量均增加(P<0.05);A+L组去甲肾上腺素、多巴胺的含量均增加(P<0.05);与L组比较,A+L组去甲肾上腺素、多巴胺的含量均降低(P<0.05)。
5 TH阳性细胞数与C组、L组、A+L组棘波持续时间呈正相关,直线回归方程为Y=0.52X-18.65 R2=0.99。
6三组TH阳性细胞数与T2大鼠脑细胞外液去甲肾上腺素、多巴胺的含量呈正相关关系,直线回归方程分别为Y=3.5X+230.28 R2=1.00;Y=8.87X+7.47 R2=1.00。
7 T2大鼠脑细胞外液去甲肾上腺素、多巴胺的含量与棘波持续时间呈正相关关系,直线回归方程分别为Y=0.15X-52.33 R2=0.98;Y=0.06X-19.11 R2=0.99。
8 L组T1与T2去甲肾上腺素、多巴胺含量的比较L组T1去甲肾上腺素含量358.9±9.12ng/ml,多巴胺319.35±6.64ng/ml, T2去甲肾上腺素、多巴胺含量与T1比较明显升高(P<0.05)
9 A+L组T1与T2去甲肾上腺素、多巴胺含量的比较A+L组T1去甲肾上腺素含量357.63±10.58ng/ml,多巴胺319.83±8.58ng/ml,T2去甲肾上腺素、多巴胺含量与T1比较明显升高(P<0.05)
结论:
1利多卡因致大鼠惊厥过程中纹状体脑细胞外液NE、DA均升高,其原因可能是神经元TH免疫活性增强。
2 DA在利多卡因致大鼠惊厥过程中起着更重要的作用
3 NE对利多卡因致大鼠惊厥有抑制作用。
Objective: In order to determine the contention of NE and DA in extracellular fluid in striatum of rats with convulsion,we make a model of lidocaine-induced convulsion. TH immunoactivity and change of concentration of NE and DA are observed, AMPT and desipramine were injected to investigate different role of norepinephrine and dopamine in the process of lidocaine-induced convulsion in striatum in rats.
Methods: Twenty-four male wistar rats weighing 250±20mg were randomly divided into 4 groups(n=6 . After anesthetized by isoflurane, a rat was placed in the stereotaxic frame and a microdialysis probe was placed into the striatum (A–1.2cm, M–2.8cm, D 3.5mm, from bregma and dural surface). Microdialysis samples were collected per 20 min after EEG waves were stable. (1) group L: After saline was injected i.p, lidocaine was single pumped into femoral vein for 30 min, and pumped at a rate of 4mg·kg-1·min-1 if multiple high-voltage spikes could not be seen. (2) group C: The process was same with group L except lactated Ringer Solution was pumped into femoral vein. (3) group A+L: The process was same with group L except AMPT was pumped into femoral vein. (4) group D+L: The process was same with group L except desipramine was pumped into femoral vein. After collecting microdialysis samples,rats were perfused and fixed through cardia. Tissue sections of brain tissue were underwent antigen recovering and droping agent and DAB, TH positive immunoactive neurons were observed under high power field of optical microscope. The concentrations of extracellular norepinephrine and dopamine in striatum and the recolleting rate of microdialysis probe were detected by the method of HPLC-fluorescence, according to recolleting rate and reforming relation of dopamine hydrochloride with dopamine to calculate concentrations of NE and DA in striatum in rats.
Results:
1 Results of respiratory depression and spikes Group D+L lasting time of respiratory depression was significantly shortencompared with group L (P<0.05). Group A+L and group D+L lasting time of multiple high-voltage spikes were significantly shorten compared with group L (P<0.05 ).
2 Results of TH immunoactivity in substantia nigra
TH positive immunoactive neurons in group A+L were significantly decreased compared with group L (P<0.05). TH positive immunoactive neurons in group A+L were significantly increased compared with group C (P<0.05).
3 Concentration of NE and DA in T2
Concentrations of NE and DA in group A+L were significantly decreased compared with group L (P<0.05)., Concentrations of NE and DA in group A+L were significantly increased compared with group C (P<0.05 each). There were significant differences among them (P<0.05).
4 Relation of each index
TH positive immunoactive neurons were directly correlated with spikes lasting time, Y=0.52X-18.65 R2=0.99. TH positive immunoactive neurons were directly correlated with concentrations of NE and DA in T2, Y=3.5X+230.28 R2=1.00 Y=8.87X+7.47 R2=1.00. Spikes lasting time were directly correlated with concentrations of NE and DA in T2, Y=0.15X-52.33 R2=0.99; Y=0.06X-19.11 R2=0.99.
5 Concentrations of NE and DA in T2 compared with T1
Concentrations of NE and DA in T2 were significantly increased compared with that in T1 in group L(P<0.05). Concentrations of NE and DA in T2 were significantly increased compared with that in T1 in group A+L (P<0.05 each).
Conclusion:
1 Concentrations of NE and DA in extracellular fluid in striatum in rats were increased during lidocain-induced convulsion. The increase of NE and DA may be attribute to activation of TH .
2 DA play a importent role in convulsion induced by lidocaine.
3 NE may play a depressant role in convulsion induced by lidocaine.
引文
1 Paxinos G, Watson C1 The Rat Brain in Stereotaxic Coordinates [M]1 San Diego , CA , USA : Academic Press , 1986,1: Figure311
2 Yoshitake T, Kehr J, Yoshitake S, et al. Determination of serotonin, noradrenaline, dopamine and by columnliquid chromatography with fluorescence detection following derivatization with benzylamine and 1,2-diphenylethylene –diamine. Chromatogr, 2006, 807: 177~183
3 Dixon CE, Flinn P, Bao J, et al. Nerve growth factor attenuates cholinergic deficits following traumatic brain injury in rats. Exp Neurol ,1997,146(2) : 479~ 490
4 Masataka Y, Masahisa H, Hiroshi G. Clonidine does not affect lidocaine seizure threshold in rats. Canjanaesth, 1993, 40(12): 1205~1209
5 Alfred E, Ciarlone. Alteration of lidocaine-or procaine-induced convulsions by manipulation of brain amines. Dent Res, 1981, 60(2): 182~186
6 Kitayama T, Song L, Morita K, et al. Down-regulation of norepinephrine transporter function induced by chronic administration of desipramine linking to the alteration of sensitivity of local-anesthetics-induced convulsions and the counteration by co-administration with local anesthetics. Brain Research, 2006, 4(33): 97~103
7 鲁燕侠,崔佳,蔺兴遥. RP-HPLC-荧光检测法测定小 鼠脑组织中 5 种神经递质的含量. 解放军药学学报, 2003, 19(4): 262~263
8 吴安石,岳云,龙健晶,等. 不同浓度异氟醚对大鼠大脑皮层乙酰胆碱含量的影响. 中华麻醉学杂志,2005,25(11):832~834
9 Lin K, Dei ZZ, Li HH, et al. Environmental cues associated with morphine modulate release of glutamate and γ-aminobutyric acid in ventral subiculum. Neuroscience Bulletin, 2006, 22(5): 255~260
10 Yoshitake T, Kehr J, Yoshitake S, et al. Determinationof serotonin, noradrenaline, dopamine and their metabo-lites in rat brain extracts and microdialysis samples bycolumnliquid chromatography with fluorescence detecti-on followingderivatization with benzylamine and 1,2-di--phenylethylenediamine. Chromatogr, 2006, 807: 177~183
11 Bradley kN, Fatiha z, neugebauer V, et al. Epile-ptogenesis up-regulates metabotropic glutamate receptor activation of sodium-calcium exchange current in the amygdala. The American Physiological Society, 2000, 2458~2462
12 Goodman JC , Valadka AB , Gopinath SP , et al. Lactate and excitatory amino acids measured by microdialysis are decreased by pentobarbital coma in head injured patients. Neurotrauma , 1996, 13 (10): 549~556
13 王天成, 孙 磊, 宋为明等.豚鼠脑在体微透析液氨基酸 A ccQ ·Tag HPLC 荧光测定法.现代检验医学杂志, 2006, 11(21): 18~20
14 Watanabe Y, Dohi S, La H, et al. The effects of bupivacaine and ropivacaine on baroreflex sensitivity with or without respiratory acidosis and alkalosis in rats. Anesth Analg, 1997, 84(2): 398
15 A ndrew BD, L arry PK, W illinam FS, et al. Tyro sine amelio rates some effects of lower body negative p ressure stress. Physio Behav, 1995, 57 (2) : 223
16 Kath leen RM , Kurt RR, Terw illiger JW , et al. Coo rdinate regulation of the cyclic AM P system w ith firing rate and exp ression oftyro sine hydroxylase in the rat locus coerules: effects of ch ronicstress and drug treatments. J N eurochem, 1992, 58 (2) : 494
17 Ohmura S, Kawada M, Ohta T, et al. Systemic toxicity and resuscitation in bupivacaine-, levobupivacaine-, or ropivacaine-infused rats. Anesth Analg, 2002, 94(2): 479
18 Chang DH, Ladd LA, Wilson KA, Gelgor L, et al. Tolerobility of large dose of intravenous levobupivacaine in sheep. Anesth Analg. 2000, 91: 671-679
19 Liu P, Feldaman HS, Giasis R, et al. Comparative CNStoxicity of Locain, entidocain, bupivacaine, and tetracain in awake dogs following rapid intravenous administration. Anesth Analg, 1983, 62: 375-379
20 徐世元.局麻药的中枢神经系统毒性与临床治疗展望.国外医学·麻醉学与复苏分册,2002,23(4):195-197
21 周仁龙. 局麻药的毒性及其防治措施进展. 实用疼痛学杂志,2007,2,3(1):64-68
22 段世明主编,麻醉药理学,1990: 147
23 Mcnamara JO, Bonhaus DW, Crain BJ, et al. Biochemical and pharmacologic studies of neurotransmitters in the kinding model. Neurotransmitters and Epilepsy, 1987, 115~160
24 Rafal M, Toni S. Genetic deletion of the noyepinephrine transporter decreases vulnerability to seizures. Neurosci Lett, 2005, 382(1-2): 51~55
25 Eisenhofer G. Plasma norepinephrine for examination of extraneuronal uptake and metabolismof norepinephrine in rats. Auton Pharmacol , 1994, 349 (3) : 259~269
26 Goldstein M. Regulatory mechanisms of dopaminebiosyn-thesis at the tyrosine hydroxylase step. Pharm Pharmac-ol , 1973 , 25 : 351
27 Zigmond RE. Acute regulation of tyrosine hydroxylase by nerve activity and by neurotransmitters viaphosphory-lation. Ann Rev Neurosci, 1989, 12: 133~137
28 Campbell DG. Identification of four phosphorylation sites inthe N terminal region of tyrosine hydroxylase. Biol Chem , 1986 , 261 : 10489
1 1 Moore JM,Liu SS,Neal JM,et al. Premedication with fentanyl and midazo 2 lam decreases the reliability of intravenous lidocaine test dose. Anesth Analg, 1998, 86(5): 1015
2 Miller RD. Anesthesia, 2001, 491
3 McFarlone C. Anesth Analg, 1994, 78: 278
4 Itzhak Y. Pharmacol Toxicol, 1994, 74(3): 162
5 Heavner JE. Reg Anesth, 1996, 21(3): 243
6 Shi B. Anesth Analg, 1997, 84: 804
7 Itzhak Y. Neurpharmacology, 1996, 35(8): 1065
8 Przegalinskki E, Tatarczynska E, Chojnacka Wojcik E. The influence of the benzodiazepine receptor antagonistflumazenil on the anxiplytic2like effectsofCGP37849 an-d ACPC in rats. Neuropharmacology, 2000, 39: 1858
9 杜冬萍,庄心良,郑吉健等.利多卡因对大鼠海马锥体神经元 GABAA-CL-电流的影响.复旦学报(医学版),2003,30(5):496~498
10 Sztark F, Thicoipe M,Favarel-Carrighes JF, et al. The use of 0.25% lidocaine with fentanyl and pancuronium for intravenous regionsl anesthesia. Anesth Analg, 1997,84: 777~779
11 Mcnamara JO, Bonhaus DW, Crain BJ, et al. Biochemical and pharmacologic studies of neurotransmitters in th-e kinding model. Neurotransmitters and Epilepsy, 1987:115~160
12 Rafal M, Toni S. Genetic deletion of the noyepinephrine transporter decreases vulnerability to seizures. Neurosci Lett, 2005, 382(1-2): 51~55
13 颜梅,戴体俊.吸入麻醉药抗药物惊厥的实验研究.深圳医学院学报, 2003, 23(5): 377~379
14 孟晶,戴体俊,段世明等.依托咪酯抗实验性惊厥作用及其机制.徐州医学院学报,2006, 26(1): 21~23
15 kasaba T. Rcg Anesth Pain Med, 1998, 23(1): 71
16 张继国,张静,徐晓燕等.氯胺酮对利多卡因化学性点燃大鼠的抑制作用.泰山医学院学报, 2005, 6(26)526~527
17 Hiroshi E, Yuichi K, Hiroshi B, et al. Effect of anticon-vulsants on local anesthetic-induced neurotocity in ra-ts. Pharmacology Toxicology, 2000, 86: 59~62
18 岳旺,张芳,王蕾等.中枢a2去甲肾上腺素受体在点燃模 型的调控作用.中国药学杂志,2001,3(36):164~167
19 Czuczwar SJ. European Journal of Pharmacology, 1994, 264:103
20 Watanabe Y, Dohi S, Lida H, et al. The effects of bupivacsine and ropivacaine on baroreflex sensitivity with or without respiratory acidosis and alkalosis in rats. Anesth Analg, 1997, 84: 398~304
21 Whittington RA, Virag L, Vulliemoz Y, et al. Dexmedetomi- dine increases the cocaine seizure threshold in rats. Anesthe- siology, 2002, 97: 693~700
2 Yoshitake T, Kehr J, Yoshitake S, et al. Determination of serotonin, noradrenaline, dopamine and by columnliquid chromatography with fluorescence detection following derivatization with benzylamine and 1,2-diphenylethylene –diamine. Chromatogr, 2006, 807: 177~183
3 Dixon CE, Flinn P, Bao J, et al. Nerve growth factor attenuates cholinergic deficits following traumatic brain injury in rats. Exp Neurol ,1997,146(2) : 479~ 490
4 Masataka Y, Masahisa H, Hiroshi G. Clonidine does not affect lidocaine seizure threshold in rats. Canjanaesth, 1993, 40(12): 1205~1209
5 Alfred E, Ciarlone. Alteration of lidocaine-or procaine-induced convulsions by manipulation of brain amines. Dent Res, 1981, 60(2): 182~186
6 Kitayama T, Song L, Morita K, et al. Down-regulation of norepinephrine transporter function induced by chronic administration of desipramine linking to the alteration of sensitivity of local-anesthetics-induced convulsions and the counteration by co-administration with local anesthetics. Brain Research, 2006, 4(33): 97~103
7 鲁燕侠,崔佳,蔺兴遥. RP-HPLC-荧光检测法测定小 鼠脑组织中 5 种神经递质的含量. 解放军药学学报, 2003, 19(4): 262~263
8 吴安石,岳云,龙健晶,等. 不同浓度异氟醚对大鼠大脑皮层乙酰胆碱含量的影响. 中华麻醉学杂志,2005,25(11):832~834
9 Lin K, Dei ZZ, Li HH, et al. Environmental cues associated with morphine modulate release of glutamate and γ-aminobutyric acid in ventral subiculum. Neuroscience Bulletin, 2006, 22(5): 255~260
10 Yoshitake T, Kehr J, Yoshitake S, et al. Determinationof serotonin, noradrenaline, dopamine and their metabo-lites in rat brain extracts and microdialysis samples bycolumnliquid chromatography with fluorescence detecti-on followingderivatization with benzylamine and 1,2-di--phenylethylenediamine. Chromatogr, 2006, 807: 177~183
11 Bradley kN, Fatiha z, neugebauer V, et al. Epile-ptogenesis up-regulates metabotropic glutamate receptor activation of sodium-calcium exchange current in the amygdala. The American Physiological Society, 2000, 2458~2462
12 Goodman JC , Valadka AB , Gopinath SP , et al. Lactate and excitatory amino acids measured by microdialysis are decreased by pentobarbital coma in head injured patients. Neurotrauma , 1996, 13 (10): 549~556
13 王天成, 孙 磊, 宋为明等.豚鼠脑在体微透析液氨基酸 A ccQ ·Tag HPLC 荧光测定法.现代检验医学杂志, 2006, 11(21): 18~20
14 Watanabe Y, Dohi S, La H, et al. The effects of bupivacaine and ropivacaine on baroreflex sensitivity with or without respiratory acidosis and alkalosis in rats. Anesth Analg, 1997, 84(2): 398
15 A ndrew BD, L arry PK, W illinam FS, et al. Tyro sine amelio rates some effects of lower body negative p ressure stress. Physio Behav, 1995, 57 (2) : 223
16 Kath leen RM , Kurt RR, Terw illiger JW , et al. Coo rdinate regulation of the cyclic AM P system w ith firing rate and exp ression oftyro sine hydroxylase in the rat locus coerules: effects of ch ronicstress and drug treatments. J N eurochem, 1992, 58 (2) : 494
17 Ohmura S, Kawada M, Ohta T, et al. Systemic toxicity and resuscitation in bupivacaine-, levobupivacaine-, or ropivacaine-infused rats. Anesth Analg, 2002, 94(2): 479
18 Chang DH, Ladd LA, Wilson KA, Gelgor L, et al. Tolerobility of large dose of intravenous levobupivacaine in sheep. Anesth Analg. 2000, 91: 671-679
19 Liu P, Feldaman HS, Giasis R, et al. Comparative CNStoxicity of Locain, entidocain, bupivacaine, and tetracain in awake dogs following rapid intravenous administration. Anesth Analg, 1983, 62: 375-379
20 徐世元.局麻药的中枢神经系统毒性与临床治疗展望.国外医学·麻醉学与复苏分册,2002,23(4):195-197
21 周仁龙. 局麻药的毒性及其防治措施进展. 实用疼痛学杂志,2007,2,3(1):64-68
22 段世明主编,麻醉药理学,1990: 147
23 Mcnamara JO, Bonhaus DW, Crain BJ, et al. Biochemical and pharmacologic studies of neurotransmitters in the kinding model. Neurotransmitters and Epilepsy, 1987, 115~160
24 Rafal M, Toni S. Genetic deletion of the noyepinephrine transporter decreases vulnerability to seizures. Neurosci Lett, 2005, 382(1-2): 51~55
25 Eisenhofer G. Plasma norepinephrine for examination of extraneuronal uptake and metabolismof norepinephrine in rats. Auton Pharmacol , 1994, 349 (3) : 259~269
26 Goldstein M. Regulatory mechanisms of dopaminebiosyn-thesis at the tyrosine hydroxylase step. Pharm Pharmac-ol , 1973 , 25 : 351
27 Zigmond RE. Acute regulation of tyrosine hydroxylase by nerve activity and by neurotransmitters viaphosphory-lation. Ann Rev Neurosci, 1989, 12: 133~137
28 Campbell DG. Identification of four phosphorylation sites inthe N terminal region of tyrosine hydroxylase. Biol Chem , 1986 , 261 : 10489
1 1 Moore JM,Liu SS,Neal JM,et al. Premedication with fentanyl and midazo 2 lam decreases the reliability of intravenous lidocaine test dose. Anesth Analg, 1998, 86(5): 1015
2 Miller RD. Anesthesia, 2001, 491
3 McFarlone C. Anesth Analg, 1994, 78: 278
4 Itzhak Y. Pharmacol Toxicol, 1994, 74(3): 162
5 Heavner JE. Reg Anesth, 1996, 21(3): 243
6 Shi B. Anesth Analg, 1997, 84: 804
7 Itzhak Y. Neurpharmacology, 1996, 35(8): 1065
8 Przegalinskki E, Tatarczynska E, Chojnacka Wojcik E. The influence of the benzodiazepine receptor antagonistflumazenil on the anxiplytic2like effectsofCGP37849 an-d ACPC in rats. Neuropharmacology, 2000, 39: 1858
9 杜冬萍,庄心良,郑吉健等.利多卡因对大鼠海马锥体神经元 GABAA-CL-电流的影响.复旦学报(医学版),2003,30(5):496~498
10 Sztark F, Thicoipe M,Favarel-Carrighes JF, et al. The use of 0.25% lidocaine with fentanyl and pancuronium for intravenous regionsl anesthesia. Anesth Analg, 1997,84: 777~779
11 Mcnamara JO, Bonhaus DW, Crain BJ, et al. Biochemical and pharmacologic studies of neurotransmitters in th-e kinding model. Neurotransmitters and Epilepsy, 1987:115~160
12 Rafal M, Toni S. Genetic deletion of the noyepinephrine transporter decreases vulnerability to seizures. Neurosci Lett, 2005, 382(1-2): 51~55
13 颜梅,戴体俊.吸入麻醉药抗药物惊厥的实验研究.深圳医学院学报, 2003, 23(5): 377~379
14 孟晶,戴体俊,段世明等.依托咪酯抗实验性惊厥作用及其机制.徐州医学院学报,2006, 26(1): 21~23
15 kasaba T. Rcg Anesth Pain Med, 1998, 23(1): 71
16 张继国,张静,徐晓燕等.氯胺酮对利多卡因化学性点燃大鼠的抑制作用.泰山医学院学报, 2005, 6(26)526~527
17 Hiroshi E, Yuichi K, Hiroshi B, et al. Effect of anticon-vulsants on local anesthetic-induced neurotocity in ra-ts. Pharmacology Toxicology, 2000, 86: 59~62
18 岳旺,张芳,王蕾等.中枢a2去甲肾上腺素受体在点燃模 型的调控作用.中国药学杂志,2001,3(36):164~167
19 Czuczwar SJ. European Journal of Pharmacology, 1994, 264:103
20 Watanabe Y, Dohi S, Lida H, et al. The effects of bupivacsine and ropivacaine on baroreflex sensitivity with or without respiratory acidosis and alkalosis in rats. Anesth Analg, 1997, 84: 398~304
21 Whittington RA, Virag L, Vulliemoz Y, et al. Dexmedetomi- dine increases the cocaine seizure threshold in rats. Anesthe- siology, 2002, 97: 693~700