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:10618859
- 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 PainAdultAnalgesicsAnimalsAnticoagulationAttenuatedCalcium ChannelCellsCentral Nervous SystemChronicClinicalCocaineComplementConduction AnesthesiaConstipationDangerousnessDataDevelopmentDiseaseDoseDrug abuseElectron MicroscopyElectrophysiology (science)Exposure toFamilyGeneral PopulationGeneral anesthetic drugsHeroinHyperalgesiaImpaired cognitionKnockout MiceKnowledgeLaboratoriesLocal AnestheticsMediatingMedicalModalityModelingMusNarcoticsNeurologicNeuronsNociceptionNociceptorsNumbnessOperative Surgical ProceduresOpiate AddictionOpioidOpioid AnalgesicsOutcomePainPain managementPathogenesisPathologicPathway interactionsPatientsPerioperativePeripheralPersonsPharmaceutical PreparationsPhysiologicalPopulationPosterior Horn CellsPostoperative PainPostoperative PeriodPreparationPresynaptic TerminalsPropertyProtein IsoformsPublishingRattusResearchRiskRisk ReductionRodent ModelRoleSensory Motor PerformancesSiteSkinSliceSpinalSpinal CordSpinal GangliaSurgical incisionsSynapsesSynaptic TransmissionSynaptic VesiclesT-Type Calcium ChannelsTestingThioctic AcidTissuesTranslatingUnited StatesUnited States National Center for Health StatisticsUrinary RetentionVentilatory DepressionVertebral columnVeteransWorkabuse liabilityaddictionantinociceptionchronic painclinically relevantcognitive functiondietary supplementsdorsal hornin vivoin vivo Modelinhibitorinnovationmembermilitary veteranmouse modelneuronal excitabilityneurophysiologynovel therapeuticsopioid abuseoverdose deathpain modelpain processingpharmacologicpreclinical studypresynaptic neuronspreventresponseside effecttissue injurytransmission processvoltagevoltage gated channel
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)的痛觉感觉神经元可以变得敏感
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
CasubV/sub3.1 T-type calcium channels are important for spatial memory processing in the dorsal subiculum
卡苏布 V 亚基 3.1 T 型钙通道对背侧海马下托中的空间记忆处理很重要
- DOI:
10.1016/j.neuropharm.2022.109400 - 发表时间:
2023-03-15 - 期刊:
- 影响因子:4.600
- 作者:
Srdjan M. Joksimovic;Seyed Mohammadreza Ghodsi;Jasper A. Heinsbroek;James E. Orfila;Nicolas Busquet;Vesna Tesic;Robert Valdez;Brier Fine-Raquet;Vesna Jevtovic-Todorovic;Yogendra H. Raol;Paco S. Herson;Slobodan M. Todorovic - 通讯作者:
Slobodan M. Todorovic
CaV2.3 channels in the mouse central medial thalamic nucleus are essential for thalamocortical oscillations and spike wave discharges
小鼠中央内侧丘脑核中的 CaV2.3 通道对于丘脑皮质振荡和棘波放电至关重要
- DOI:
10.1038/s41598-025-87795-x - 发表时间:
2025-02-10 - 期刊:
- 影响因子:3.900
- 作者:
Vasilije P. Tadic;Tamara Timic Stamenic;Slobodan M. Todorovic - 通讯作者:
Slobodan M. Todorovic
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
Neuropathic pain: role for presynaptic T-type channels in nociceptive signaling
神经病理性疼痛:突触前 T 型通道在伤害性信号传导中的作用
- DOI:
10.1007/s00424-012-1211-y - 发表时间:
2013-01-16 - 期刊:
- 影响因子:2.900
- 作者:
Slobodan M. Todorovic;Vesna Jevtovic-Todorovic - 通讯作者:
Vesna Jevtovic-Todorovic
Sex-specific hypnotic effects of the neuroactive steroid (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile are mediated by peripheral metabolism into an active hypnotic steroid
神经活性甾体(3β,5β,17β)-3-羟基雄烷-17-腈的性别特异性催眠作用是通过外周代谢为活性催眠甾体介导的。
- DOI:
10.1016/j.bja.2022.09.025 - 发表时间:
2023-02-01 - 期刊:
- 影响因子:9.200
- 作者:
Francesca M. Manzella;Omar H. Cabrera;Davis Wilkey;Brier Fine-Raquet;Jelena Klawitter;Kathiresan Krishnan;Douglas F. Covey;Vesna Jevtovic-Todorovic;Slobodan M. Todorovic - 通讯作者:
Slobodan M. Todorovic
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:
9891793 - 财政年份:2020
- 资助金额:
-- - 项目类别:
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