全身麻醉中枢作用部位及电生理学研究
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摘要
全身麻醉作用机理研究已有百年的历史，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。近年来发现了一种c-fos基因，为神经元的第三信使参与重要脑活动的表达，是一种脑功能活动形态学定位法，利用神经元受到某种刺激其c-fos基因的表达急剧增加，与此相关结构的神经元胞浆内mRNA很快进入胞核转录形成Fos蛋白，用免疫组织化学方法能显示与麻醉作用相关的多级神经元的位置。本文用c-fos基因免疫组化方法，研究全麻药在中枢神经系统的作用部位；周免疫组化双标法，研究吸入麻醉药中枢作用部位的有关神经递质；用膜片钳技术，研究全麻醉药对部分功能核团神经元放电频率和对GABA_A受体耦联的Cl~(-1)通道的关系，为进一步探讨全麻机理提供形态学和电生理学依据。
研究结果：
1．Fos蛋白表达 吸入麻醉剂安氟醚、异氟醚、氟烷和甲氧氟烷麻醉在中枢Fos阳性神经元主要位于端脑、间脑和脑干。主要分布于：端脑为杏仁核(Ce)核族、伏核(ACB)、外侧隔核(LS)、中纹床核(BST)、梨状皮层(Pir)、海马CAI、Ⅱ和海马回溴觉小岛(ICJ)；间脑为缰核(Hb)、丘脑室旁核(Pv)、中央杏仁核(Cm)、丘脑菱形核(Rh)、丘脑再连合核(Re)、背外侧膝状核(DLG)、背内侧梨状核(DEN)、丘脑外侧背核(LD)、丘脑腹外侧核(LP)、下丘脑室旁核(Pe)、中视前核(MnPo)、视上核(So)、视交叉上核(Sch)、弓状核(Arc)、丘脑腹后外侧核(VPL)；脑干为中脑导水管周围灰质(PAG)、脚间核(IP)、EW核(E-W)和缝际尾侧核(CLI)及脊髓背角(DH)共27个Fos阳性核团。且Fos阳性神经元的数目随着吸入麻醉剂的浓度增加面增多，表明这些阳性神经元确实参与了吸入麻醉过程。
静脉麻醉剂硫喷妥钠麻醉1h后，Fos阳性神经元大多分布在Pir、ACB、BL、LS、LHb、Pe、PV、腹下膝状核(VLG)、DEn，SO，SCh、腹前视前核(AVPO)、Icj、弧束核(Sol)和乳头上核(SuM) 15
The mechanism of general anesthesia has been studied for about 150 years. But its functional sites has not been clarified so far, primarily due to the fact that no method has been found fit to display the mysterious state of general anesthesia in the central nervous system. In the past few years, quite a number of papers have suggested that activation of immediate early genes (IEG, Proto-oncogenes) such as c-fos oncogene, called the third messenger, participate in message transmission in the central neuron action. When the central neuron was stimulated , the expression of fos protein increased rapidly in the related neurones which can be detected by immunohistochemical technique .The present paper aims at: (1) Locating the functional site of general anesthesia in central nervous system with immunohistochemical single-labeled method;(2)Detectmining the related neurotransmitters with immunohistochemical double labeled method; (3)Studying the effects of general anesthesia on the spontantaneous neural discharge and Cl~(-1) chennel of functional neurones from rat hypothalamic slices with whole cell patch clamp.
RESULTS 1.Fos protein expression
The Fos-positive neuron induced by enflurane, isoflurane, methaxyflurane and halothane anesthesia were mainly situated in the telencephalon, diencephalon and brain stem. They appeared mostly in telencephalon, including amygdaloid nuclear complex, accumbens nucleus(ABC), laterodorsal thalamic nucleus(LD), lateral septal nucleus(LS)), bed nucleus of the stlia terminal is(BST), piliform cortex(Pir), field CAl of Ammon's horn (CAl) and islands of calleja(Icj) ; in diencephalon, including habenular nucleus(Hb),
研究结果：
1．Fos蛋白表达 吸入麻醉剂安氟醚、异氟醚、氟烷和甲氧氟烷麻醉在中枢Fos阳性神经元主要位于端脑、间脑和脑干。主要分布于：端脑为杏仁核(Ce)核族、伏核(ACB)、外侧隔核(LS)、中纹床核(BST)、梨状皮层(Pir)、海马CAI、Ⅱ和海马回溴觉小岛(ICJ)；间脑为缰核(Hb)、丘脑室旁核(Pv)、中央杏仁核(Cm)、丘脑菱形核(Rh)、丘脑再连合核(Re)、背外侧膝状核(DLG)、背内侧梨状核(DEN)、丘脑外侧背核(LD)、丘脑腹外侧核(LP)、下丘脑室旁核(Pe)、中视前核(MnPo)、视上核(So)、视交叉上核(Sch)、弓状核(Arc)、丘脑腹后外侧核(VPL)；脑干为中脑导水管周围灰质(PAG)、脚间核(IP)、EW核(E-W)和缝际尾侧核(CLI)及脊髓背角(DH)共27个Fos阳性核团。且Fos阳性神经元的数目随着吸入麻醉剂的浓度增加面增多，表明这些阳性神经元确实参与了吸入麻醉过程。
静脉麻醉剂硫喷妥钠麻醉1h后，Fos阳性神经元大多分布在Pir、ACB、BL、LS、LHb、Pe、PV、腹下膝状核(VLG)、DEn，SO，SCh、腹前视前核(AVPO)、Icj、弧束核(Sol)和乳头上核(SuM) 15
The mechanism of general anesthesia has been studied for about 150 years. But its functional sites has not been clarified so far, primarily due to the fact that no method has been found fit to display the mysterious state of general anesthesia in the central nervous system. In the past few years, quite a number of papers have suggested that activation of immediate early genes (IEG, Proto-oncogenes) such as c-fos oncogene, called the third messenger, participate in message transmission in the central neuron action. When the central neuron was stimulated , the expression of fos protein increased rapidly in the related neurones which can be detected by immunohistochemical technique .The present paper aims at: (1) Locating the functional site of general anesthesia in central nervous system with immunohistochemical single-labeled method;(2)Detectmining the related neurotransmitters with immunohistochemical double labeled method; (3)Studying the effects of general anesthesia on the spontantaneous neural discharge and Cl~(-1) chennel of functional neurones from rat hypothalamic slices with whole cell patch clamp.
RESULTS 1.Fos protein expression
The Fos-positive neuron induced by enflurane, isoflurane, methaxyflurane and halothane anesthesia were mainly situated in the telencephalon, diencephalon and brain stem. They appeared mostly in telencephalon, including amygdaloid nuclear complex, accumbens nucleus(ABC), laterodorsal thalamic nucleus(LD), lateral septal nucleus(LS)), bed nucleus of the stlia terminal is(BST), piliform cortex(Pir), field CAl of Ammon's horn (CAl) and islands of calleja(Icj) ; in diencephalon, including habenular nucleus(Hb),
引文
1．刘俊杰 主编 现代麻醉学 人民卫生出版社,1997年第二版第一次印刷
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5. Wamil AW, et al. Halothane alters electrical activity and calcium dynamics in cultured mouse cortical, spinal cord, and dorsal root ganglion neurons. Neurosci-Lett, 1996; 216(2): 93
6. Pocok G and Richards CD .Excitatory and inhibitory synapyic mechanisms in anesthesia. Br j Anaesth, 1993;71:148
7. Griffiths R and Norman RI. Effects of anaesthetics on uptake , synthesis and release of transmitter. Br j Anesth.1993;71:96
8. Chan-CK, et al . Differential inhibition of lysophosphatidate signaling by volatile anesthetics. Anesthesiology. 1997; 86 (3): 660
9. Flohr H. An information processing theory of anaesthesia. Neuropsychologia,1995; 48 (4):1169
10.Franks NP,et al. Molecular and cellular mechanisms of general anaesthesia. Nature. 1994; 367 (17): 607
11.Anget A. Central neuronal pathways and the process of aneasthsia. Br j Anaesth . 1993;71:148
12. Krnjevic-K . Cellular and synaptic actions of general anaesthetics. Gen-Pharmacol. 1992 ; 23(6): 965
13.Mazzanti-L; Lenaz-G; Marinelli-F; et al .Structural and functional modifications induced by ketamine on synaptosomes in the rat. Neuropharmacology. 1991 ; 30 (12A): 1343
14.Little HJ. How has molecular pharmacology contributed to our understanding of the mechanism of general anesthesia? Pharmacol- Ther, 1996;69 (1): 37
15.Cantor RS. The lateral pressure profile in membranes: a physical mechanism of general anesthesia. Biochemistry , 1997; 36 (9): 2339
16.Cantor-RS .The lateral pressure profile in membranes: a physical mechanism of general anesthesia. Biochemistry. 1997 ; 36(9): 2339
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2. Kress HG. Molecular and cellular actions of inhalation anesthetics . Anesthesiol INS, 1992; (2): 293
3. Franks NP, Lieb WR. Molecular and cllular mechanisms of general anesthesia. Nature, 1994; 367: 607
4. Roth SH and Miller KW. Molecular and cellar mechanisms of anesthetics. New York, Plenum Medical Book Company, 1986;PP: 3
5. Wamil AW, et al. Halothane alters electrical activity and calcium dynamics in cultured mouse cortical, spinal cord, and dorsal root ganglion neurons. Neurosci-Lett, 1996; 216(2): 93
6. Pocok G and Richards CD .Excitatory and inhibitory synapyic mechanisms in anesthesia. Br j Anaesth, 1993;71:148
7. Griffiths R and Norman RI. Effects of anaesthetics on uptake , synthesis and release of transmitter. Br j Anesth.1993;71:96
8. Chan-CK, et al . Differential inhibition of lysophosphatidate signaling by volatile anesthetics. Anesthesiology. 1997; 86 (3): 660
9. Flohr H. An information processing theory of anaesthesia. Neuropsychologia,1995; 48 (4):1169
10.Franks NP,et al. Molecular and cellular mechanisms of general anaesthesia. Nature. 1994; 367 (17): 607
11.Anget A. Central neuronal pathways and the process of aneasthsia. Br j Anaesth . 1993;71:148
12. Krnjevic-K . Cellular and synaptic actions of general anaesthetics. Gen-Pharmacol. 1992 ; 23(6): 965
13.Mazzanti-L; Lenaz-G; Marinelli-F; et al .Structural and functional modifications induced by ketamine on synaptosomes in the rat. Neuropharmacology. 1991 ; 30 (12A): 1343
14.Little HJ. How has molecular pharmacology contributed to our understanding of the mechanism of general anesthesia? Pharmacol- Ther, 1996;69 (1): 37
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