T-type calcium channel inhibitors and alpha lipoic acid as novel therapies for treating pain post-surgery
T型钙通道抑制剂和α硫辛酸作为治疗术后疼痛的新疗法
基本信息
- 批准号:9891793
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:Absence of pain sensationAcuteAcute PainAdultAfferent NeuronsAnalgesicsAnimalsAttenuatedCalcium ChannelCellsChronicClinicalCocaineComplementConduction AnesthesiaConstipationDangerousnessDataDevelopmentDiseaseDoseDrug abuseElectron MicroscopyElectrophysiology (science)Exposure toFamilyGeneral PopulationGeneral anesthetic drugsHeroinHyperalgesiaImpaired cognitionKnockout MiceKnowledgeLaboratoriesLeadLocal AnestheticsMediatingMedicalModalityModelingMusNarcoticsNeuraxisNeurologicNeuronsNociceptionNociceptorsNumbnessOperative Surgical ProceduresOpiate AddictionOpioidOpioid AnalgesicsOutcomePainPain managementPathogenesisPathologicPathway interactionsPatientsPerioperativePeripheralPharmaceutical PreparationsPharmacologyPhysiologicalPopulationPosterior Horn CellsPostoperative PainPostoperative PeriodPreparationPresynaptic TerminalsPropertyProtein IsoformsPublishingRattusResearchRiskRodent ModelRoleSensory Motor PerformancesSiteSkinSliceSpinalSpinal CordSpinal GangliaSurgical incisionsSynapsesSynaptic TransmissionSynaptic VesiclesT-Type Calcium ChannelsTestingThioctic AcidTissuesTranslatingUnited StatesUnited States National Center for Health StatisticsUrinary RetentionVentilatory DepressionVeteransWorkaddictionbasechronic painclinically relevantcognitive functiondietary supplementsdorsal hornin vivoin vivo Modelinhibitor/antagonistinnovationmembermouse modelneuronal excitabilityneurophysiologynovel therapeuticsopioid abuseoverdose deathpain modelpain processingpreclinical studypreventresponseside effecttissue injurytransmission processvoltage
项目摘要
Pain-sensing sensory neurons of the dorsal root ganglion (DRG) and dorsal horn (DH) can become sensitized
(hyperexcitable) in response to the tissue injury. Because of insufficient knowledge about the mechanisms for
this sensitization, current treatment for postoperative pain has been limited to somewhat non-specific systemic
drugs (opioids) having significant side effects or potential for abuse. Recent studies in our laboratory have
established that CaV3.2 (T-type) calcium-channels voltage-gated calcium channels make a previously
unrecognized contribution to sensitization of pain responses by enhancing excitability of peripheral nociceptors
in the setting of surgically induced tissue injury. Despite the established role of CaV3.2 channels in the
pathogenesis of peripheral sensitization of pain responses, the role of multiple isoforms of T-channels (CaV3.1,
CaV3.2 and CaV3.3) in central (spinal) sensitization of pain responses is not well studied. We previously showed
that the blockade of CaV3.2 currents in nociceptive DRG neurons by an endogenous compound and dietary
supplement a lipoic acid (ALA) underlies its potent peripheral anti-nociceptive effects. Our new data demonstrate
that ALA displays excellent analgesia in a rat model of post-surgical pain resulting from paw skin incisions, and
that CaV3.1 isoform of T-channels is also important for the development of hyperalgesia in a mouse model of
paw incision. Thus, we propose that ALA may represent a safer class of analgesics having desirable analgesic
properties in post-operative period by targeting T-channels in pain pathway, as well as being able to reduce the
risk for the opioid addiction.
In Aim 1, we will study the roles of CaV3.1 and CaV3.2 channels in ALA-induced analgesia using a clinically
relevant rodent model of skin and deep tissue incision.
In Aim 2, we will define the role of ALA in modulating synaptic transmission and neuronal excitability of
nociceptive DH neurons. In this Aim, we will also test the hypothesis that ALA may reverse hyperexcitability in
the identified nociceptive DH neurons in the rats following plantar skin incision. These studies will define the
whole-cell neurophysiological effects of ALA in the major nociceptive pathway. Finally, we will also use electron
microscopy to study cellular and subcellular localization of CaV3.1 and CaV3.2 channels in nociceptive DH
neurons. The proposed work is innovative and medically significant because we anticipate that our preclinical
studies will identify novel therapies for perioperative pain that may greatly decrease the need for narcotics and
potential for drug abuse.
背根神经节(DRG)和背角(DH)的疼痛感应感官神经元可以变得敏感
响应组织损伤的响应。由于对机制的知识不足
术后疼痛的当前治疗的这种敏感性仅限于某种非特异性的全身性
药物(阿片类药物)具有重大副作用或滥用潜力。我们实验室的最新研究
确定Cav3.2(T型)钙通道电压门控钙通道使得先前
通过增强周围伤害感受器的兴奋性,对疼痛反应的敏感性的贡献无法识别
在手术诱导的组织损伤的情况下。尽管Cav3.2渠道在
疼痛反应的周围敏化发病机制,T通道多种同工型的作用(Cav3.1,
Cav3.2和cav3.3)在中央(脊柱)疼痛反应的敏化中没有很好地研究。我们以前显示了
通过内源性化合物和饮食中的伤害感受DRG神经元中Cav3.2电流的阻断
补充脂酸(ALA)是其有效的外围抗伤害感受作用的基础。我们的新数据证明了
ALA在爪皮切口引起的术后疼痛的大鼠模型中表现出极好的镇痛
T通道的CAV3.1同工型对于在小鼠模型中的痛风发展也很重要
爪切口。因此,我们建议ALA可能代表具有理想镇痛药的更安全的镇痛药
术后期间通过靶向疼痛途径中的T通道,并能够减少
阿片类药物成瘾的风险。
在AIM 1中,我们将使用临床上研究Cav3.1和Cav3.2通道在ALA诱导的镇痛中的作用
相关的皮肤和深层组织切口模型。
在AIM 2中,我们将定义ALA在调节突触传播和神经元兴奋性中的作用
伤害性DH神经元。在此目标中,我们还将检验以下假设:ALA可能会逆转
足底皮肤切口后,大鼠中鉴定出的伤害性DH神经元。这些研究将定义
ALA在主要伤害性途径中的全细胞神经生理作用。最后,我们还将使用电子
研究伤害性DH中Cav3.1和Cav3.2通道的细胞和亚细胞定位的显微镜
神经元。拟议的工作具有创新性和具有医学意义,因为我们预计我们的临床前
研究将确定围手术期疼痛的新型疗法,这可能会大大减少对麻醉品的需求和
滥用药物的潜力。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Slobodan M. Todorovic其他文献
1342: Increased Excitability of Voltage-Gated Sodium Channels in a Rat Model of Bladder Outlet Obstruction
- DOI:
10.1016/s0022-5347(18)38567-7 - 发表时间:
2004-04-01 - 期刊:
- 影响因子:
- 作者:
Adam P. Klausner;Slobodan M. Todorovic;Jeremy B. Tuttle;William D. Steers - 通讯作者:
William D. Steers
Slobodan M. Todorovic的其他文献
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{{ truncateString('Slobodan M. Todorovic', 18)}}的其他基金
Voltage-gated calcium channels as target for anesthetics
电压门控钙通道作为麻醉靶点
- 批准号:
10402374 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Voltage-gated calcium channels as target for anesthetics
电压门控钙通道作为麻醉靶点
- 批准号:
10620169 - 财政年份:2021
- 资助金额:
-- - 项目类别:
In vivo dual color imaging of neuronal networks during anesthesia
麻醉期间神经元网络的体内双色成像
- 批准号:
10582000 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Voltage-gated calcium channels as target for anesthetics
电压门控钙通道作为麻醉靶点
- 批准号:
10205852 - 财政年份:2021
- 资助金额:
-- - 项目类别:
T-type calcium channel inhibitors and alpha lipoic acid as novel therapies for treating pain post-surgery
T型钙通道抑制剂和α硫辛酸作为治疗术后疼痛的新疗法
- 批准号:
10454791 - 财政年份:2020
- 资助金额:
-- - 项目类别:
T-type calcium channel inhibitors and alpha lipoic acid as novel therapies for treating pain post-surgery
T型钙通道抑制剂和α硫辛酸作为治疗术后疼痛的新疗法
- 批准号:
10618859 - 财政年份:2020
- 资助金额:
-- - 项目类别:
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