Effects of anesthetics on thalamic excitability
Effects of anesthetics on thalamic excitability
批准号:
9764914
负责人:
Slobodan M. Todorovic
金额:
$33.04万
依托单位国家:
美国
项目类别:
财政年份:
2014
资助国家:
美国
项目状态:
已结题
起止时间:
2014-01-01 至 2023-06-30
关键词:
AcuteAdjuvantAnesthesia proceduresAnestheticsAnimal ModelAnimalsArousalBinding SitesBiophysicsBrainCalciumCalcium ChannelCategoriesCell NucleusCellsCentral Medial Thalamic NucleusChildClinicalClinical ResearchCognitive deficitsDataDevelopmentDrug TargetingExposure toGeneral AnesthesiaGeneral anesthetic drugsGeneticGoalsGrantHumanHypnosisIn VitroIsofluraneKetamineLaboratory FindingLearning DisabilitiesLifeLigandsMedicalMolecularMusN-Methyl-D-Aspartate ReceptorsN-MethylaspartateNerve DegenerationNeuronsOperative Surgical ProceduresPathologicPharmacologyPropertyPropofolProtein IsoformsRattusRecombinantsResearchRiskRodentRoleSedation procedureSensorySleepSliceT-Type Calcium ChannelsTestingThalamic NucleiThalamic structureUnconscious StateWorkchannel blockersclinical effectclinical practiceclinically relevantdensitygamma-Aminobutyric Acidhypnoticin vivoinhibitor/antagonistinnovationknock-downneuronal excitabilityneurotoxicneurotoxicitynonhuman primatenovelnovel strategiespatch clamppatient populationpupreceptorsevofluranevoltage
中文摘要
项目摘要
丘脑是感觉信息从外周流向皮层和大脑的主要通道。
丘脑皮质连接中断可能是安眠药催眠作用的一个基本共同特征
全身麻醉剂(气)多。此外,最近的研究确定了中央银行的重要作用
丘脑的内侧核(CEM)和腹基底核(VB)控制觉醒和自然睡眠。
尽管丘脑T型钙通道(T通道)在自然睡眠中的作用相当好
虽然已被证实,但这些通道在麻醉中的作用仍然知之甚少。另外,在过去
在这项资助的周期中,我们确定了大鼠仔鼠暴露于临床相关气体中会导致T-
丘脑网状核(NRT)的电流密度,进而导致持久的超兴奋性
以及在体外和体内丘脑皮质网络的病理性振荡。神经元的这些变化
选择性拮抗T通道可逆转其功能。
我们推测,使用针对T通道的药物抑制剂可能会促进GA诱导的丢失
因此,可能会减少手术所需的有效挥发性气体的使用。整体而言
这项应用的目的是检验中心假设,即T通道的CaV3.1亚型在
丘脑CEM和Vb核在麻醉催眠中起重要作用。
为了验证这一假设,我们将使用急性脑片和重组人的体外膜片钳记录。
选择性CEM和Vb核的体外细胞和体内脑电记录
药理T通道抑制剂,以及具有全球和区域特异性沉默的小鼠遗传学
丘脑中的CaV3.1通道追求以下特定目标:
目的1:确定重组和天然CaV3.1通道的生物物理和分子机制
异氟醚(ISO)和七氟烷(SEVO)两种常见气体的体外抑制作用及其对神经细胞的影响
CEM的区域兴奋性。我们还将使用新的方法与ISO的光亲和配体(AZI-ISO)和
SEVO(AZI-SEVO)以确定挥发性气体在CaV3.1通道上的特定分子结合位点。
目的2:确定大脑中皮层CaV3.1通道是否参与丘脑皮质的改变
挥发性气体镇静催眠及选择性T通道给药过程中的网络功能
抑制剂TTA-P2,通过活体脑电记录进行评估。
目的3:确定CEM和Vb丘脑CaV3.1通道的区域特异性沉默是否会
ISO和Sevo对体内镇静催眠和丘脑皮质振荡的不同影响
这项拟议的工作是创新的,因为麻醉剂引起的意识丧失的新机制将是
特色化的。它具有重要的医学意义,因为它描述了靶向电压门控的药物的重要性
钙通道的潜在发展更安全的做法在临床麻醉。
英文摘要
Project Summary
The thalamus is the major gateway for the flow of sensory information from the periphery to the cortex and the
disruption of thalamocortical connectivity may be an essential common feature of the hypnotic effects of
many general anesthetic (GAs). Furthermore, recent studies have identified important roles of the central
medial nucleus (CeM) and ventrobasal (VB) nucleus of the thalamus in control of arousal and natural sleep.
Although the role of thalamic T-type calcium channels (T-channels) in natural sleep is reasonably well
established, the role of these channels in anesthesia remains poorly understood. In addition, in the past
cycle of this grant we established that exposure of rat pups to clinically-relevant GAs causes increased T-
current densities in the reticular thalamic nucleus (nRT), which in turn contributes to lasting hyperexcitabil- ity
and pathological oscillations in thalamocortical networks in vitro and in vivo. These changes in neuronal
function were reversed by selective antagonism of T-channels.
We postulate that the use of pharmacological inhibitors that target T-channels may facilitate GA-induced loss
of consciousness and hence may reduce usage of potent volatile GAs needed for surgery. The overall
objective of this application, is to test the central hypothesis that the CaV3.1 isoform of T-channels in the
CeM and VB thalamic nuclei is important for anesthetic-induced hypnosis.
To test this hypothesis, we will use in vitro patch-clamp recordings from acute brain slices and recombinant
cells in vitro and electroencephalographic (EEG) recordings in vivo from the CeM and VB nuclei, selective
pharmacological T-channel inhibitors, and mouse genetics with global and region-specific silencing of
CaV3.1 channels in the thalamus to pursue the following specific aims:
Aim 1: To determine the biophysical and molecular mechanism of recombinant and native CaV3.1 channel
inhibition in vitro by two common GAs, isoflurane (ISO) and sevoflurane (SEVO), and their effect on neu-
ronal excitability of CeM. We will also use new approach with photoaffinity ligands of ISO (AZI-ISO) and
SEVO (AZI-SEVO) to identify specific molecular binding sites on CaV3.1 channels for volatile GAs.
Aim 2: To determine whether CaV3.1 channels in the CeM contribute to the alterations in thalamocortical
network function during sedation/hypnosis with volatile GAs and administration of the selective T-channel
inhibitor TTA-P2, as assessed by in vivo EEG recordings.
Aim 3: To determine if region-specific silencing of CaV3.1 channels in the CeM and VB thalamus will have
differential effects on sedation/hypnosis and thalamocortical oscillations in vivo induced by ISO and SEVO.
The proposed work is innovative in that new mechanisms of anesthetic-induced loss of consciousness will be
characterized. It is medically significant because it describes the importance of drugs that target voltage- gated
calcium channels for potential development of safer practices in clinical anesthesia.
期刊论文(0)
专著(0)
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会议论文
Voltage-gated calcium channels as target for anesthetics
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批准号:10402374
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项目类别:
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资助金额:$48.98万
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财政年份:2021
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负责人:Slobodan M. Todorovic
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依托单位:
Voltage-gated calcium channels as target for anesthetics
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批准号:10620169
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In vivo dual color imaging of neuronal networks during anesthesia
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批准号:10582000
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资助金额:$16.18万
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财政年份:2021
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Voltage-gated calcium channels as target for anesthetics
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批准号:10205852
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资助金额:$46.27万
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财政年份:2021
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负责人:Slobodan M. Todorovic
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依托单位:
T-type calcium channel inhibitors and alpha lipoic acid as novel therapies for treating pain post-surgery
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批准号:10454791
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项目类别:
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资助金额:$0.0万
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财政年份:2020
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负责人:Slobodan M. Todorovic
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依托单位:
T-type calcium channel inhibitors and alpha lipoic acid as novel therapies for treating pain post-surgery
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批准号:10618859
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项目类别:
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资助金额:$0.0万
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财政年份:2020
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负责人:Slobodan M. Todorovic
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依托单位:
T-type calcium channel inhibitors and alpha lipoic acid as novel therapies for treating pain post-surgery
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批准号:9891793
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资助金额:$0.0万
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财政年份:2020
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负责人:Slobodan M. Todorovic
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依托单位:
Effects of anesthetics on thalamic excitability
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批准号:9200392
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资助金额:$30.71万
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财政年份:2014
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依托单位:
Effects of anesthetics on thalamic excitability
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批准号:9245704
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项目类别:
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资助金额:$30.71万
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财政年份:2014
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负责人:Slobodan M. Todorovic
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依托单位:
The role of trace metals and T-channels in pain
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批准号:8633031
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项目类别:
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资助金额:$19.75万
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财政年份:2013
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负责人:Slobodan M. Todorovic
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依托单位:
The role of trace metals and T-channels in pain
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批准号:8534373
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项目类别:
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资助金额:$19.75万
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财政年份:2013
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负责人:Slobodan M. Todorovic
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依托单位:
REDOX PHARMACOLOGY OF T CHANNELS IN DRG NEURONS
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批准号:7942245
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项目类别:
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资助金额:$16.08万
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财政年份:2009
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负责人:Slobodan M. Todorovic
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依托单位:
REDOX PHARMACOLOGY OF T CHANNELS IN DRG NEURONS
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批准号:7631340
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项目类别:
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资助金额:$28.21万
-
财政年份:2006
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负责人:Slobodan M. Todorovic
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依托单位:
REDOX PHARMACOLOGY OF T CHANNELS IN DRG NEURONS
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批准号:7208052
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项目类别:
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资助金额:$28.22万
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财政年份:2006
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负责人:Slobodan M. Todorovic
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依托单位:
REDOX PHARMACOLOGY OF T CHANNELS IN DRG NEURONS
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批准号:7090964
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项目类别:
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资助金额:$29.08万
-
财政年份:2006
-
负责人:Slobodan M. Todorovic
-
依托单位:
REDOX PHARMACOLOGY OF T CHANNELS IN DRG NEURONS
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批准号:7439132
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项目类别:
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资助金额:$28.21万
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财政年份:2006
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负责人:Slobodan M. Todorovic
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依托单位:
Anesthetics block neuronal voltage-gated Ca2+ currents
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批准号:7025092
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项目类别:
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资助金额:$27.14万
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财政年份:2005
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负责人:Slobodan M. Todorovic
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依托单位:
Anesthetics block neuronal voltage-gated Ca2+ currents
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批准号:7198084
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项目类别:
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资助金额:$26.35万
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财政年份:2005
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负责人:Slobodan M. Todorovic
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依托单位:
Anesthetics block neuronal voltage-gated Ca2+ currents
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批准号:6872769
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项目类别:
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资助金额:$26.38万
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财政年份:2005
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负责人:Slobodan M. Todorovic
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依托单位:
Anesthetics block neuronal voltage-gated Ca2+ currents
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批准号:7578342
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项目类别:
-
资助金额:$26.35万
-
财政年份:2005
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负责人:Slobodan M. Todorovic
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依托单位:
海外基金