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Consciousness and Anesthesia Takashi Mashimo (Graduate School of Medicine) 眞下 節(医学系研究科麻酔 集中治療医学・教室)
・ General Anesthesia
・ Anesthesia and EEG
・ Mechanism of Anesthesia
-GABAA Receptor-
General Anesthesia
Operation without
Anesthesia
First Anesthesia with Ether by Dr. Morton in 1846
A Patient under General Anesthesia
Purpose of General Anesthesia
• Amnesia and Unconsciousness
• Immobility with Surgical Stimuli
• Suppression of Stress Responses to Surgical Stimuli
Three Requisites for General Anesthesia
• Sedative, Hypnotic (Anesthetic)
• Analgesic (Opioid)
• Muscle Relaxant
Inhalational Anesthetics
Anesthesia Machine
Intravenous Anesthetics
Continuous Infusion of Propofol and Remifentanyl
Components of the Anesthetized State
• General anesthesia consists of several components.
• Some of the discrete brain regions and neural circuits are involved in specific components of the anesthetized state.
• General anesthetics interact with subpopulations of nervous system cells to create each of the separate properties of anesthesia
Main Components of General Anesthesia
• Sedation (鎮静、思考力低下)• Amnesia (記憶消失)• Unconsciousness, Hypnosis (無意識)• Analgesia (無痛)• Immobility (不動化)• Adrenergic Suppression (交感神経抑制)
Rudolph & Antkowiak: Nature Reviews Neuroscience 5: 709, 2004
Sites in the CNS that are thought to be involved in the anesthetic components; sedative, hypnotic
and immobilizing actions of propofol
Correlation between propofol level and anesthetic depth
Dose-response Curves of Main Components
of General Anesthesia
ED50s of Dose-response Curves of Anesthetic Components:
Amnesia < Unconsciousness < Immobility < Adrenergic Suppression
How do Anesthetics Produce the Broad Effects throughout the Brain ?
• Individual aspects of the anesthetized state are attributable to different sets of nerve cells, which are themselves distinguished by specific surface proteins (receptors) that interact with anesthetics.
• New compounds designed to target just those proteins, and hence the desirable effects of anesthetics –as well as sedatives, sleep aids and memory drugs.
Anesthesia and EEG
Arousal (Consciousness)
and
Anesthesia (Unconsciousness)
Unconsciousness (Hypnosis)
• Mechanism of arousal (consciousness) is complex.
• Centers of arousal are thought to be frontal cortex, thalamus and midbrain reticular formation.
• It is difficult to pinpoint a single anatomical source of unconsciousness during anesthesia.
• Unconsciousness is simply the result of cognitive unbinding: a severing of communication between the many brain regions that cooperate in higher cognition processing.
GABAA Receptor and EEG
10Hz spindle wave
Activation of GABAA receptor with general anestheticsGABAA Receptor
Increase in amplitude of 10Hz spindle wave
Electroencepharogram (EEG)
EEG is thought to originate in the cone cells of cerebral cortex.
①
Cerebral Cortex
Thalamus
Dendrite of Cone Cell
Cone Cell
++
++
--
- -- -
-
-
++
Stages of Sleep and EEG
• Stage 2: 10Hz spindle waves• Stage 3: 2Hz slow waves (20~50%)• Stage 4: 2Hz slow waves (over 50%)
Changes in EEG during Anesthesia
1 sec
Low amplitude
Awake/light anesthesia: low amplitude rapid wave
5Hz
1 sec
High amplitude
Moderate anesthesia: high amplitude slow wave10Hz
BIS (EEG) Electrode during Anesthesia
BIS = 80
BIS = 60
BIS = 40
低振幅速波
高振幅徐波( α wave )
Burst & suppression
Flat EEG
BIS value100
0
80
60
40
20
Awake
Moderate anesthesia
Deep anesthesia
Too deep anesthesiaBIS = 0
Sevoflurane Anesthesia and EEG
+50
0
- 50
4(sec)
+50
0
- 50
4(sec)
+50
0
- 50
4(sec)
高振幅徐波 ( δwave ) BIS=15
+50
0
- 50
4(sec)
Light anesthesia
+50
0
- 50
4(sec)
Power Spectrum of EEG
① ②
① 10Hz
② 2Hz
2% sevoflurane anesthesia
Power spectrum of EEG
EEG Power Spectra during Sevoflurane Anesthesia
Sevoflurane 1.0%BIS 61
Sevoflurane 1.5%BIS 53
Sevoflurane 2.0%BIS 46
2Hz 10Hz
EEG Power Spectra during Sevoflurane Anesthesia in Infants and Adults
Infant
Adult
1.0% 1.5% 2.0% 2.5% 3.0%
Concentration of sevoflurane (%)
Sevoflurane Concentrations in Which an Amplitude of the EEG’s 10Hz wave Reaches the Highest
P<0.05
2.3±0.3% 1.8±0.4%
Infant Adult
Sevoflurane
(%)
Mechanism of General Anesthesia
The effect of anesthesia is analogous to pulling out plugs at the switchboard in the brain
• Unconsciousness is simply the result of cognitive unbinding: a severing of communication between the many brain regions that cooperate in higher cognition processing.
• If one imagines groups of neurons as forming lines in a vast telephone network, the effect of general anesthesia is analogous to pulling out plugs at the switchboard.
Anesthetics interacts with multiple varieties of specific proteins, known as receptors, on the surface of neurons
Receptors and Anesthetics• Anesthetics interacts with multiple varieties of
specific proteins, known as receptors, on the surface of neuron cells.
• Families of receptors contain different versions which tend to predominate in different areas of the CNS. The presence of particular receptor subtypes on only certain subpopulations of neurons will determine which cells are influenced by an anesthetic.
• Receptor variants are the targets of current anesthetic drugs, understanding how the drugs interact with the receptors to change the cell’s function and how those cellular changes produce the components of anesthesia.
GABA and GABAA Receptor
• GABA is an inhibitory neurotransmitter, which has the ability to block neuronal communication
• It helps to maintain overall balance in the CNS by dampening neuron’ ability to respond to excitatory messages from other cells.
• GABAA receptor is thought to play a central part in the actions of anesthetics
Orser BA, Sci Am, June:32-9,2007
GABAA receptor plays a central part in the actions of anesthetics
• Anesthetics increases the function of GABAA receptors by interacting at discrete binding cavities or attaching to specific amino acids in the receptors themselves.
• Anesthetics prolong the chloride ion channel opening, which causes hyperpolarization of the cell membrane.
• It extends the inhibitory effects of GABA molecules bound to the receptor.
Anesthetics and GABA:Changing ChargeOrser BA, Sci Am, June:32-9,2007
Anesthetics bind the GABAA receptor and prolonging the channel opening, which causes hyperpolarization of the cell membrane
GABAA Receptor
• GABAA receptor is a protein complex composed of five subunit parts, which can be mixed and matched in various combinations.
• At least 19 different GABAA receptor subunits exists in mammals, and most of those have variant subtypes.
• Most GABAA receptors are composed of 2 alpha subunits, 2 betas and 1 gamma.
GABAA Receptor’s Subunit Composition
The GABAA receptor’s subunit composition dramatically alters its pharmacological properties: just one subunit difference within a GABAA receptor’s structure can determine whether and how it will respond to a particular anesthetic drug.
Anesthetics is Jamming Nervous Transmission
• Anesthetics dampen neuronal communication, in part, by enhancing the effects of neurotransmitter GABA, a signaling molecule that inhibits nerve cells from firing.
• Current research is focused on how the anesthetics interact with cellular GABAA receptors to block neural activity.
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神経受容体発現と電気生理学的測定神経受容体発現と電気生理学的測定
2電極電位固定2電極電位固定法法
Xenopus Xenopus oocyteoocyte
に組み込プラスミドに組み込プラスミドみみ
大腸菌内で大大腸菌内で大量に増殖量に増殖
プラスミドを収プラスミドを収穫し,制限酵素穫し,制限酵素で直線化で直線化
部位プロモーター部位プロモーターより翻訳より翻訳
アフリカツメガエルアフリカツメガエル卵へ注入卵へ注入
24-4824-48 時間培時間培養養
Rudolph & Antkowiak: Nature Reviews Neuroscience 5: 709, 2004 より引用
Amino-acid Point Mutations in β2(N265S) Mice and β3(N265M) Mice
Unconsciousness
Rudolph & Antkowiak: Nature Reviews Neuroscience 5: 709, 2004 より引用
Behavioural Responses to Intravenous Anesthetics in β3(N265M) Mice and β2(N265S) Mice
Effects of Volatile Anesthetics on Ligand-gated Ion ChannelsEffects of Volatile Anesthetics on Ligand-gated Ion Channels
サブタイプ
Halothane Isoflurane Sevoflurane
5-HT3 受容体
5-HT3A
Potentiation Potentiation Inhibition
神経性
α4
β2Inhibition Inhibition Inhibition
nACh 受容体 α7 Inhibition No effect
骨格筋 αβγδ
Little inhibition
Little inhibition
Little inhibition
GABAA 受容体
Potentiation Potentiation Potentiation
NMDA 受容体 Inhibition Inhibition InhibitionMachu et al. J Pharmacol Exp Ther Machu et al. J Pharmacol Exp Ther
19941994Jenkins et al. Br J Pharmacol 1996Jenkins et al. Br J Pharmacol 1996Violet JM et al. Anesthesiology 1997
Flood P et al. Anesthesiology 1997Jenkins A et al. Anesthesiology 1999Hollmann MW et al. Anesth Analg 2001
Effects of Gaseous Anesthetics on Ligand-gated Ion ChannelsEffects of Gaseous Anesthetics on Ligand-gated Ion Channels
サブタイプ
N2O Xe
5-HT3 受容体
5-HT3A
Inhibition Inhibition
神経性
α4β2 Inhibition Inhibition
nACh 受容体 α7 Inhibition Inhibition
骨格筋 αβγδ
GABAA 受容体
No effect Potentiation
No effect Potentiation
NMDA 受容体 Inhibition Inhibition
Yamakura et al. Anesthesiology 2000Yamakura et al. Anesthesiology 2000
Suzuki et al. Anesth Analg 2003Suzuki et al. Anesth Analg 2003