七氟烷对GAD67-GFP基因敲入小鼠脑内GABA神经元激活作用及GABA_A受体作用的研究
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摘要
全身麻醉作用机理研究已有160多年的历史,特别是中枢作用部位,至今仍然是国内外麻醉学界十分关注而又悬而未决的研究课题。
研究目的:本研究目的旨在应用分子生物学、免疫组化及免疫荧光双标等多种先进的神经科学技术,以GAD67-GFP基因敲入小鼠为研究对象,系统观察在吸入麻醉药七氟烷的作用下,脑内GABA神经元被激活的部位及其GABAA受体参与的部位及细胞内机制。为进一步阐明全身麻醉中枢作用机理提供新的证据。
研究方法:
第一部分:成年雄性GAD67-GFP基因敲入小鼠随机分为3组:C组(C Group)空白对照组;S1组(S1 Group):浅麻醉状态(Incomplete anesthesia state)组,即小鼠反正反射消失但不超过30秒;S2组(S2 Group):深麻醉状态(Complete anesthesia state)组,即反正反射完全消失30s以上。各组GAD67-GFP基因敲入小鼠达到预设麻醉状态后,取脑制取脑薄片(片厚30μm),分别进行Fos免疫组化染色、GABA神经元和Fos蛋白的免疫荧光双标染色,在激光共聚焦显微镜下进行观察计数;并快速取出GAD67-GFP基因敲入小鼠海马和丘脑,制备RNA,反转录合成cDNA ,设计合成c-Fos基因mRNA序列相应的特异性引物,实施荧光定量PCR检测,所有PCR产物经琼脂糖凝胶电泳鉴定。
第二部分:c57野生小鼠实验分组同第一部分,设计合成GABAA受体α4亚单位特异性引物,实施GABAA受体α4亚单位荧光定量PCR检测,同时进行GABAA受体与Fos免疫荧光双标染色,在激光共聚焦显微镜下进行观察计数
研究结果:
第一部分:七氟烷对GAD67-GFP基因敲入小鼠脑内GABA神经元激活作用的研究
1.对GAD67-GFP基因敲入小鼠脑内Fos蛋白表达的影响结果表明:吸入麻醉药七氟烷能诱导GAD67-GFP基因敲入小鼠脑内皮质(Cg1,Cg2)、海马(CA1,DG)、下丘脑背内侧核(DM)、中脑导水管周围灰质(PAG)、丘脑室旁核(PV)、外侧隔核(LS)等部位Fos的表达,与C组相比明显增多(P<0.05),随麻醉深度增加S2组比S1组Fos蛋白表达增多(P<0.05)。还发现在杏仁核中间部(MeA)、E-W核(E-W nucleus)、弓状核(Arc)和下丘脑室旁核腹侧核(PaV)等部位Fos表达仅出现在S2组。
2.对GAD67-GFP基因敲入小鼠海马和丘脑Fos mRNA的影响荧光定量PCR结果表明c-fos mRNA在海马和丘脑部位S1和S2组表达与对照组相比明显上调(P<0.01),并且S2组上调更多与S1组相比有显著差异(P<0.01)。
3.对GAD67-GFP基因敲入小鼠脑内GABA和Fos共存表达的影响免疫荧光双标结果表明:在外侧隔核(LS)几乎所有的Fos都存在于GABA神经元内,并且在S2组中共存于GABA神经元内的Fos与S1组相比明显增多。在海马(CA1, DG),下丘脑背内侧核(DM),皮质(Cg1, Cg2)和中脑导水管周围灰质(PAG),仅有少部分的Fos存在于GABA神经元内,大部分Fos表达于GABA神经元之外。PV有较多的Fos表达,但并没有GABA神经元存在。而在PaV、MeA、Arc及E-W这几个部位的S2组中也有Fos表达,但是在这几个神经核团中几乎没有Fos共存于GABA神经元内。
第二部分:七氟烷对野生c57小鼠脑内GABAA受体作用的研究
1.对野生c57小鼠脑内GABAA受体α4亚单位mRNA表达的影响.在小鼠脑干和丘脑部位GABAA受体α4亚单位mRNA表达S1和S2组与对照组相比显著升高(P<0.01),S2组与S1组相比显著升高(P<0.01)。
2.对野生c57小鼠脑内GABAA受体蛋白表达的影响免疫荧光结果表明:S1和S2组在脑干和丘脑内GABAA受体蛋白与Fos蛋白共存表达与对照组相比明显增加,并且S2组与S1组相比明显增加(P<0.05)。
研究结论:
1.吸入麻醉药七氟烷能诱导Fos蛋白和c-fos mRNA在GAD67-GFP基因敲入小鼠脑内多个核团神经元呈阳性表达,且表达的数量随七氟烷麻醉深度增加而增多。
2.吸入麻醉药七氟烷能诱导GAD67-GFP基因敲入小鼠脑内相关核团GABA神经元和Fos存在明显的共存现象,也具有部位差异及显著的浓度相关关系。
3.吸入麻醉药七氟烷能诱导野生c57小鼠脑干和丘脑GABAA受体与Fos共存表达且具有浓度相关性。
以上结论可证明吸入麻醉药七氟烷能够浓度相关性的激活小鼠脑内不同部位的GABA神经元,并且通过GABAA受体将抑制信号通过细胞内c-fos基因传递出来。
Objective: The mechanisms underlying volatile anesthesia agents are not well elucidated. Emerging researches have focused on the participation ofγ-aminobutyric acid (GABA) neurons but there still lacks morphological evidence. To elucidate the possible activation of GABAergic neurons by sevoflurane inhalation, Fos and green fluorescent protein (GFP) double labeling were used on the brain of glutamic acid decarboxylase (GAD) 67-GFP knock-in mice after sevoflurane inhalation. Methods: Twenty GAD67-GFP knock-in mice were divided into 3 groups: S1 group: incomplete anesthesia state induced by sevoflurane; S2 group: complete anesthesia induced by sevoflurane; control(C) group. Results 1. Real-time PCR and immunohistochemistry results indicated that sevoflurane induced a significant increase of c-fos mRNA in thalamus and hippocampus and protein expression in the dorsomedial hypothalamic nucleus (DM), periaqueductal grey (PAG), hippocampus (CA1, DG), paraventricular thalamic nucleus (PV), lateral septal nucleus (LS), cingulate cortex (Cg1, Cg2) in S1 and S2 group compared with the control group. These alterations on Fos expression were dose-dependent. In S2 group, Fos was only expressed in the amygdale, Edinger-Westphal (E-W) nucleus, arcuate hypothalamic nucleus (Arc) and the ventral part of paraventricular hypothalamic nucleus (PaV). 2. Double immunofluroscent staining indicated that in LS,almost all Fos were present in GABAergic neurons. In CA1, DG, DM, cg1, cg2 and PAG, Fos was expressed as well, but only few were present in GABAergic neurons. Fos expression was very high in paraventricular thalamic nucleus, but no coexistence were found as no GABAergic neuron was detected in this area. 3.The real-time PCR results indicated that in brain stem and thalamus the GABAA receptorα4 subtype mRNA expression upregulated significantly in S1 and S2 groups compared with C group. 4. Double immunofluroscent staining indicated that in brain stem and thalamus Fos were present in neurons that GABAA receptors were expressed in S1 and S2 groups. Conclusion: Our results provided morphological evidence that GABA neurons and GABAA receptors in speific brain areas may participate in the sevoflurane-induced anesthesia.
研究目的:本研究目的旨在应用分子生物学、免疫组化及免疫荧光双标等多种先进的神经科学技术,以GAD67-GFP基因敲入小鼠为研究对象,系统观察在吸入麻醉药七氟烷的作用下,脑内GABA神经元被激活的部位及其GABAA受体参与的部位及细胞内机制。为进一步阐明全身麻醉中枢作用机理提供新的证据。
研究方法:
第一部分:成年雄性GAD67-GFP基因敲入小鼠随机分为3组:C组(C Group)空白对照组;S1组(S1 Group):浅麻醉状态(Incomplete anesthesia state)组,即小鼠反正反射消失但不超过30秒;S2组(S2 Group):深麻醉状态(Complete anesthesia state)组,即反正反射完全消失30s以上。各组GAD67-GFP基因敲入小鼠达到预设麻醉状态后,取脑制取脑薄片(片厚30μm),分别进行Fos免疫组化染色、GABA神经元和Fos蛋白的免疫荧光双标染色,在激光共聚焦显微镜下进行观察计数;并快速取出GAD67-GFP基因敲入小鼠海马和丘脑,制备RNA,反转录合成cDNA ,设计合成c-Fos基因mRNA序列相应的特异性引物,实施荧光定量PCR检测,所有PCR产物经琼脂糖凝胶电泳鉴定。
第二部分:c57野生小鼠实验分组同第一部分,设计合成GABAA受体α4亚单位特异性引物,实施GABAA受体α4亚单位荧光定量PCR检测,同时进行GABAA受体与Fos免疫荧光双标染色,在激光共聚焦显微镜下进行观察计数
研究结果:
第一部分:七氟烷对GAD67-GFP基因敲入小鼠脑内GABA神经元激活作用的研究
1.对GAD67-GFP基因敲入小鼠脑内Fos蛋白表达的影响结果表明:吸入麻醉药七氟烷能诱导GAD67-GFP基因敲入小鼠脑内皮质(Cg1,Cg2)、海马(CA1,DG)、下丘脑背内侧核(DM)、中脑导水管周围灰质(PAG)、丘脑室旁核(PV)、外侧隔核(LS)等部位Fos的表达,与C组相比明显增多(P<0.05),随麻醉深度增加S2组比S1组Fos蛋白表达增多(P<0.05)。还发现在杏仁核中间部(MeA)、E-W核(E-W nucleus)、弓状核(Arc)和下丘脑室旁核腹侧核(PaV)等部位Fos表达仅出现在S2组。
2.对GAD67-GFP基因敲入小鼠海马和丘脑Fos mRNA的影响荧光定量PCR结果表明c-fos mRNA在海马和丘脑部位S1和S2组表达与对照组相比明显上调(P<0.01),并且S2组上调更多与S1组相比有显著差异(P<0.01)。
3.对GAD67-GFP基因敲入小鼠脑内GABA和Fos共存表达的影响免疫荧光双标结果表明:在外侧隔核(LS)几乎所有的Fos都存在于GABA神经元内,并且在S2组中共存于GABA神经元内的Fos与S1组相比明显增多。在海马(CA1, DG),下丘脑背内侧核(DM),皮质(Cg1, Cg2)和中脑导水管周围灰质(PAG),仅有少部分的Fos存在于GABA神经元内,大部分Fos表达于GABA神经元之外。PV有较多的Fos表达,但并没有GABA神经元存在。而在PaV、MeA、Arc及E-W这几个部位的S2组中也有Fos表达,但是在这几个神经核团中几乎没有Fos共存于GABA神经元内。
第二部分:七氟烷对野生c57小鼠脑内GABAA受体作用的研究
1.对野生c57小鼠脑内GABAA受体α4亚单位mRNA表达的影响.在小鼠脑干和丘脑部位GABAA受体α4亚单位mRNA表达S1和S2组与对照组相比显著升高(P<0.01),S2组与S1组相比显著升高(P<0.01)。
2.对野生c57小鼠脑内GABAA受体蛋白表达的影响免疫荧光结果表明:S1和S2组在脑干和丘脑内GABAA受体蛋白与Fos蛋白共存表达与对照组相比明显增加,并且S2组与S1组相比明显增加(P<0.05)。
研究结论:
1.吸入麻醉药七氟烷能诱导Fos蛋白和c-fos mRNA在GAD67-GFP基因敲入小鼠脑内多个核团神经元呈阳性表达,且表达的数量随七氟烷麻醉深度增加而增多。
2.吸入麻醉药七氟烷能诱导GAD67-GFP基因敲入小鼠脑内相关核团GABA神经元和Fos存在明显的共存现象,也具有部位差异及显著的浓度相关关系。
3.吸入麻醉药七氟烷能诱导野生c57小鼠脑干和丘脑GABAA受体与Fos共存表达且具有浓度相关性。
以上结论可证明吸入麻醉药七氟烷能够浓度相关性的激活小鼠脑内不同部位的GABA神经元,并且通过GABAA受体将抑制信号通过细胞内c-fos基因传递出来。
Objective: The mechanisms underlying volatile anesthesia agents are not well elucidated. Emerging researches have focused on the participation ofγ-aminobutyric acid (GABA) neurons but there still lacks morphological evidence. To elucidate the possible activation of GABAergic neurons by sevoflurane inhalation, Fos and green fluorescent protein (GFP) double labeling were used on the brain of glutamic acid decarboxylase (GAD) 67-GFP knock-in mice after sevoflurane inhalation. Methods: Twenty GAD67-GFP knock-in mice were divided into 3 groups: S1 group: incomplete anesthesia state induced by sevoflurane; S2 group: complete anesthesia induced by sevoflurane; control(C) group. Results 1. Real-time PCR and immunohistochemistry results indicated that sevoflurane induced a significant increase of c-fos mRNA in thalamus and hippocampus and protein expression in the dorsomedial hypothalamic nucleus (DM), periaqueductal grey (PAG), hippocampus (CA1, DG), paraventricular thalamic nucleus (PV), lateral septal nucleus (LS), cingulate cortex (Cg1, Cg2) in S1 and S2 group compared with the control group. These alterations on Fos expression were dose-dependent. In S2 group, Fos was only expressed in the amygdale, Edinger-Westphal (E-W) nucleus, arcuate hypothalamic nucleus (Arc) and the ventral part of paraventricular hypothalamic nucleus (PaV). 2. Double immunofluroscent staining indicated that in LS,almost all Fos were present in GABAergic neurons. In CA1, DG, DM, cg1, cg2 and PAG, Fos was expressed as well, but only few were present in GABAergic neurons. Fos expression was very high in paraventricular thalamic nucleus, but no coexistence were found as no GABAergic neuron was detected in this area. 3.The real-time PCR results indicated that in brain stem and thalamus the GABAA receptorα4 subtype mRNA expression upregulated significantly in S1 and S2 groups compared with C group. 4. Double immunofluroscent staining indicated that in brain stem and thalamus Fos were present in neurons that GABAA receptors were expressed in S1 and S2 groups. Conclusion: Our results provided morphological evidence that GABA neurons and GABAA receptors in speific brain areas may participate in the sevoflurane-induced anesthesia.
引文
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51. Schwartz AE, Maneksha FR, Kanchuger MS, Sidhu US, Poppers PJ: Flumazenil decreases the minimum alveolar concentration isoflurane in dogs. Anesthesiology 1989, 70(5):764-766.
52. Geller E, Schiff B, Halpern P, Speiser Z, Cohen S: A benzodiazepine receptor antagonist improves emergence of mice from halothane anaesthesia. Neuropharmacology 1989, 28(3):271-274.
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54. Nicoll RA: The effects of anaesthetics on synaptic excitation and inhibition in the olfactory bulb. J Physiol 1972, 223(3):803-814.
55. Galindo A: Effects of procaine, pentobarbital and halothane on synaptic transmission in the central nervous system. J Pharmacol Exp Ther 1969, 169(2):185-195.
56. Gage PW, Robertson B: Prolongation of inhibitory postsynaptic currents by pentobarbitone, halothane and ketamine in CA1 pyramidal cells in rat hippocampus. Br J Pharmacol 1985, 85(3):675-681.
57. Maclver MB TD, Mody I (ed.): Two mechanisms for anesthetic-induced enhancement of GABAA-mediated neuronal inhibition. New York: The New York Academy of Sciences; 1991.
58. Mody I, Tanelian DL, MacIver MB: Halothane enhances tonic neuronal inhibition by elevating intracellular calcium. Brain Res 1991, 538(2):319-323.
59. Jones MV, Brooks PA, Harrison NL: Enhancement of gamma-aminobutyric acid-activated Cl- currents in cultured rat hippocampal neurones by three volatile anaesthetics. J Physiol 1992, 449:279-293.
60. Wakamori M, Ikemoto Y, Akaike N: Effects of two volatile anesthetics and a volatile convulsant on the excitatory and inhibitory amino acid responses indissociated CNS neurons of the rat. J Neurophysiol 1991, 66(6):2014-2021.
61. Jones MV HL, Harrison NL: Clinical concentrations of three volatile anesthetics prolong GABA-mediated inhibitory postsynaptic currents at synapses between cultured rat hippocampal neurons. Anesthesiology 1991, 75(A):580.
62. Yeh JZ QF, Tanguy J, Nakahiro M, Narahashi T, Brunner EA. (ed.): General anesthetic action on gamma-aminobutyric acid-activated channels. New York: The New York Academy of Sciences; 1991.
63. Nakahiro M, Yeh JZ, Brunner E, Narahashi T: General anesthetics modulate GABA receptor channel complex in rat dorsal root ganglion neurons. FASEB J 1989, 3(7):1850-1854.
64.曹云飞,俞卫锋,王士雷(ed.):全麻原理及研究新进展.北京:人民军医出版社; 2006.
65. Li YQ, Takada M, Kaneko T, Mizuno N: GABAergic and glycinergic neurons projecting to the trigeminal motor nucleus: a double labeling study in the rat. J Comp Neurol 1996, 373(4):498-510.
66. Huang J. WYY, Wang W., Wei Y.Y., Li Y.Q., Wu S.X., : Preproenkephalin mRNA is expressed in a subpopulation of GABAergic neurons in the spinal dorsal hornn of the GAD67-GFP knock-in mouse. The Anat Rec 2008, 291.
67. Dudziak R, Vettermann J: [Uptaken distribution and metabolism of sevoflurane]. Anaesthesist 1996, 45 Suppl 1:S1-9.
68. Bennett RC, Fancy SP, Walsh CM, Brown AJ, Taylor PM: Comparison of sevoflurane and isoflurane in dogs anaesthetised for clinical surgical or diagnostic procedures. J Small Anim Pract 2008, 49(8):392-397.
69. Perouansky M, Hemmings HC, Pearce RA: Anesthetic effects on glutamatergic neurotransmission: lessons learned from a large synapse. Anesthesiology 2004, 100(3):470-472.
70. Franks NP, Lieb WR: Selective actions of volatile general anaesthetics at molecular and cellular levels. Br J Anaesth 1993, 71(1):65-76.
71. Banks MI, Pearce RA: Dual actions of volatile anesthetics on GABA(A) IPSCs: dissociation of blocking and prolonging effects. Anesthesiology 1999, 90(1):120-134.
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75. Aloisi AM, Zimmermann M, Herdegen T: Sex-dependent effects of formalin and restraint on c-Fos expression in the septum and hippocampus of the rat. Neuroscience 1997, 81(4):951-958.
76. Hamaya Y, Takeda T, Dohi S, Nakashima S, Nozawa Y: The effects of pentobarbital, isoflurane, and propofol on immediate-early gene expression in the vital organs of the rat. Anesth Analg 2000, 90(5):1177-1183.
77. Jenkins TA, Amin E, Brown MW, Aggleton JP: Changes in immediate early gene expression in the rat brain after unilateral lesions of the hippocampus. Neuroscience 2006, 137(3):747-759.
78. Sekine S, Matsumoto S, Issiki A, Kitamura T, Yamada J, Watanabe Y: Changes in expression of GABAA alpha4 subunit mRNA in the brain under anesthesia induced by volatile and intravenous anesthetics. Neurochem Res 2006, 31(3):439-448.
79.卢静,戴体俊,曾因明: C-fos基因表达的相关机制和意义.国外医学麻醉学与复苏学分册2004, 25(5):273-275.
80. Westphalen RI, Hemmings HC, Jr.: Volatile anesthetic effects on glutamate versus GABA release from isolated rat cortical nerve terminals: 4-aminopyridine-evoked release. J Pharmacol Exp Ther 2006, 316(1):216-223.
81. Ishizeki J, Nishikawa K, Kubo K, Saito S, Goto F: Amnestic concentrations of sevoflurane inhibit synaptic plasticity of hippocampal CA1 neurons through gamma-aminobutyric acid-mediated mechanisms. Anesthesiology 2008, 108(3):447-456.
82. Yu O, Parizel N, Pain L, Guignard B, Eclancher B, Mauss Y, Grucker D: Texture analysis of brain MRI evidences the amygdala activation by nociceptive stimuli under deep anesthesia in the propofol-formalin rat model. Magn Reson Imaging 2007, 25(1):144-146.
83. Lu J, Nelson LE, Franks N, Maze M, Chamberlin NL, Saper CB: Role of endogenous sleep-wake and analgesic systems in anesthesia. J Comp Neurol 2008, 508(4):648-662.
84. Du JH, Wang, M.Z., He, J.F.: The effect of c-fos express in arcuate hypothalamic nucleus while acupuncture. J Acupunct Res 1994, 19:39-40.
85. Mahmoudi M, Kang MH, Tillakaratne N, Tobin AJ, Olsen RW: Chronic intermittent ethanol treatment in rats increases GABA(A) receptor alpha4-subunit expression: possible relevance to alcohol dependence. J Neurochem 1997, 68(6):2485-2492.
86. Follesa P, Mancuso L, Biggio F, Mostallino MC, Manca A, Mascia MP, Busonero F, Talani G, Sanna E, Biggio G: Gamma-hydroxybutyric acid and diazepam antagonize a rapid increase in GABA(A) receptors alpha(4) subunit mRNA abundance induced by ethanol withdrawal in cerebellar granule cells. MolPharmacol 2003, 63(4):896-907.
87. McKernan RM, Whiting PJ: Which GABAA-receptor subtypes really occur in the brain? Trends Neurosci 1996, 19(4):139-143.
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90. Clark M: Sensitivity of the rat hippocampal GABA(A) receptor alpha 4 subunit to electroshock seizures. Neurosci Lett 1998, 250(1):17-20.
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50. Greiner AS, Larach DR: The effect of benzodiazepine receptor antagonism by flumazenil on the MAC of halothane in the rat. Anesthesiology 1989, 70(4):644-648.
51. Schwartz AE, Maneksha FR, Kanchuger MS, Sidhu US, Poppers PJ: Flumazenil decreases the minimum alveolar concentration isoflurane in dogs. Anesthesiology 1989, 70(5):764-766.
52. Geller E, Schiff B, Halpern P, Speiser Z, Cohen S: A benzodiazepine receptor antagonist improves emergence of mice from halothane anaesthesia. Neuropharmacology 1989, 28(3):271-274.
53. Scholfield CN: Potentiation of inhibition by general anaesthetics in neurones of the olfactory cortex in vitro. Pflugers Arch 1980, 383(3):249-255.
54. Nicoll RA: The effects of anaesthetics on synaptic excitation and inhibition in the olfactory bulb. J Physiol 1972, 223(3):803-814.
55. Galindo A: Effects of procaine, pentobarbital and halothane on synaptic transmission in the central nervous system. J Pharmacol Exp Ther 1969, 169(2):185-195.
56. Gage PW, Robertson B: Prolongation of inhibitory postsynaptic currents by pentobarbitone, halothane and ketamine in CA1 pyramidal cells in rat hippocampus. Br J Pharmacol 1985, 85(3):675-681.
57. Maclver MB TD, Mody I (ed.): Two mechanisms for anesthetic-induced enhancement of GABAA-mediated neuronal inhibition. New York: The New York Academy of Sciences; 1991.
58. Mody I, Tanelian DL, MacIver MB: Halothane enhances tonic neuronal inhibition by elevating intracellular calcium. Brain Res 1991, 538(2):319-323.
59. Jones MV, Brooks PA, Harrison NL: Enhancement of gamma-aminobutyric acid-activated Cl- currents in cultured rat hippocampal neurones by three volatile anaesthetics. J Physiol 1992, 449:279-293.
60. Wakamori M, Ikemoto Y, Akaike N: Effects of two volatile anesthetics and a volatile convulsant on the excitatory and inhibitory amino acid responses indissociated CNS neurons of the rat. J Neurophysiol 1991, 66(6):2014-2021.
61. Jones MV HL, Harrison NL: Clinical concentrations of three volatile anesthetics prolong GABA-mediated inhibitory postsynaptic currents at synapses between cultured rat hippocampal neurons. Anesthesiology 1991, 75(A):580.
62. Yeh JZ QF, Tanguy J, Nakahiro M, Narahashi T, Brunner EA. (ed.): General anesthetic action on gamma-aminobutyric acid-activated channels. New York: The New York Academy of Sciences; 1991.
63. Nakahiro M, Yeh JZ, Brunner E, Narahashi T: General anesthetics modulate GABA receptor channel complex in rat dorsal root ganglion neurons. FASEB J 1989, 3(7):1850-1854.
64.曹云飞,俞卫锋,王士雷(ed.):全麻原理及研究新进展.北京:人民军医出版社; 2006.
65. Li YQ, Takada M, Kaneko T, Mizuno N: GABAergic and glycinergic neurons projecting to the trigeminal motor nucleus: a double labeling study in the rat. J Comp Neurol 1996, 373(4):498-510.
66. Huang J. WYY, Wang W., Wei Y.Y., Li Y.Q., Wu S.X., : Preproenkephalin mRNA is expressed in a subpopulation of GABAergic neurons in the spinal dorsal hornn of the GAD67-GFP knock-in mouse. The Anat Rec 2008, 291.
67. Dudziak R, Vettermann J: [Uptaken distribution and metabolism of sevoflurane]. Anaesthesist 1996, 45 Suppl 1:S1-9.
68. Bennett RC, Fancy SP, Walsh CM, Brown AJ, Taylor PM: Comparison of sevoflurane and isoflurane in dogs anaesthetised for clinical surgical or diagnostic procedures. J Small Anim Pract 2008, 49(8):392-397.
69. Perouansky M, Hemmings HC, Pearce RA: Anesthetic effects on glutamatergic neurotransmission: lessons learned from a large synapse. Anesthesiology 2004, 100(3):470-472.
70. Franks NP, Lieb WR: Selective actions of volatile general anaesthetics at molecular and cellular levels. Br J Anaesth 1993, 71(1):65-76.
71. Banks MI, Pearce RA: Dual actions of volatile anesthetics on GABA(A) IPSCs: dissociation of blocking and prolonging effects. Anesthesiology 1999, 90(1):120-134.
72. Nishikawa K, MacIver MB: Agent-selective effects of volatile anesthetics on GABAA receptor-mediated synaptic inhibition in hippocampal interneurons. Anesthesiology 2001, 94(2):340-347.
73. Sassone-Corsi P, Sisson JC, Verma IM: Transcriptional autoregulation of the proto-oncogene fos. Nature 1988, 334(6180):314-319.
74. Santin LJ, Aguirre JA, Rubio S, Begega A, Miranda R, Arias JL: c-Fos expression in supramammillary and medial mammillary nuclei following spatial reference and working memory tasks. Physiol Behav 2003, 78(4-5):733-739.
75. Aloisi AM, Zimmermann M, Herdegen T: Sex-dependent effects of formalin and restraint on c-Fos expression in the septum and hippocampus of the rat. Neuroscience 1997, 81(4):951-958.
76. Hamaya Y, Takeda T, Dohi S, Nakashima S, Nozawa Y: The effects of pentobarbital, isoflurane, and propofol on immediate-early gene expression in the vital organs of the rat. Anesth Analg 2000, 90(5):1177-1183.
77. Jenkins TA, Amin E, Brown MW, Aggleton JP: Changes in immediate early gene expression in the rat brain after unilateral lesions of the hippocampus. Neuroscience 2006, 137(3):747-759.
78. Sekine S, Matsumoto S, Issiki A, Kitamura T, Yamada J, Watanabe Y: Changes in expression of GABAA alpha4 subunit mRNA in the brain under anesthesia induced by volatile and intravenous anesthetics. Neurochem Res 2006, 31(3):439-448.
79.卢静,戴体俊,曾因明: C-fos基因表达的相关机制和意义.国外医学麻醉学与复苏学分册2004, 25(5):273-275.
80. Westphalen RI, Hemmings HC, Jr.: Volatile anesthetic effects on glutamate versus GABA release from isolated rat cortical nerve terminals: 4-aminopyridine-evoked release. J Pharmacol Exp Ther 2006, 316(1):216-223.
81. Ishizeki J, Nishikawa K, Kubo K, Saito S, Goto F: Amnestic concentrations of sevoflurane inhibit synaptic plasticity of hippocampal CA1 neurons through gamma-aminobutyric acid-mediated mechanisms. Anesthesiology 2008, 108(3):447-456.
82. Yu O, Parizel N, Pain L, Guignard B, Eclancher B, Mauss Y, Grucker D: Texture analysis of brain MRI evidences the amygdala activation by nociceptive stimuli under deep anesthesia in the propofol-formalin rat model. Magn Reson Imaging 2007, 25(1):144-146.
83. Lu J, Nelson LE, Franks N, Maze M, Chamberlin NL, Saper CB: Role of endogenous sleep-wake and analgesic systems in anesthesia. J Comp Neurol 2008, 508(4):648-662.
84. Du JH, Wang, M.Z., He, J.F.: The effect of c-fos express in arcuate hypothalamic nucleus while acupuncture. J Acupunct Res 1994, 19:39-40.
85. Mahmoudi M, Kang MH, Tillakaratne N, Tobin AJ, Olsen RW: Chronic intermittent ethanol treatment in rats increases GABA(A) receptor alpha4-subunit expression: possible relevance to alcohol dependence. J Neurochem 1997, 68(6):2485-2492.
86. Follesa P, Mancuso L, Biggio F, Mostallino MC, Manca A, Mascia MP, Busonero F, Talani G, Sanna E, Biggio G: Gamma-hydroxybutyric acid and diazepam antagonize a rapid increase in GABA(A) receptors alpha(4) subunit mRNA abundance induced by ethanol withdrawal in cerebellar granule cells. MolPharmacol 2003, 63(4):896-907.
87. McKernan RM, Whiting PJ: Which GABAA-receptor subtypes really occur in the brain? Trends Neurosci 1996, 19(4):139-143.
88. Liu ZF, Burt DR: A synthetic standard for competitive RT-PCR quantitation of 13 GABA receptor type A subunit mRNAs in rats and mice. J Neurosci Methods 1998, 85(1):89-98.
89. Barnard EA, Skolnick P, Olsen RW, Mohler H, Sieghart W, Biggio G, Braestrup C, Bateson AN, Langer SZ: International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function. Pharmacol Rev 1998, 50(2):291-313.
90. Clark M: Sensitivity of the rat hippocampal GABA(A) receptor alpha 4 subunit to electroshock seizures. Neurosci Lett 1998, 250(1):17-20.