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

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)
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会议论文数量(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
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:
Effects of anesthetics on thalamic excitability
麻醉药对丘脑兴奋性的影响
  • 批准号:
    9200392
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:
Effects of anesthetics on thalamic excitability
麻醉药对丘脑兴奋性的影响
  • 批准号:
    9764914
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:
Effects of anesthetics on thalamic excitability
麻醉药对丘脑兴奋性的影响
  • 批准号:
    9245704
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:
The role of trace metals and T-channels in pain
微量金属和 T 通道在疼痛中的作用
  • 批准号:
    8633031
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:

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Clinical Outcome Assessments for Acute Pain Therapeutics in Infants and young Children (COA APTIC)
婴幼儿急性疼痛治疗的临床结果评估 (COA APTIC)
  • 批准号:
    10778757
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
Selective actin remodeling of sensory neurons for acute pain management
感觉神经元的选择性肌动蛋白重塑用于急性疼痛管理
  • 批准号:
    10603436
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
Clinical Outcome Assessments for Acute Pain Therapeutics in Infants and young Children (COA APTIC)
婴幼儿急性疼痛治疗的临床结果评估 (COA APTIC)
  • 批准号:
    10783106
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
Development of A Focused Ultrasound Device for Noninvasive, Peripheral Nerve Blockade to Manage Acute Pain
开发用于非侵入性周围神经阻断来治疗急性疼痛的聚焦超声装置
  • 批准号:
    10740796
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
Predicting Pediatric Sickle Cell Disease Acute Pain Using Mathematical Models Based on mHealth Data
使用基于移动健康数据的数学模型预测儿童镰状细胞病急性疼痛
  • 批准号:
    10599401
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
Non-Contingent Acute Pain Stress Drives Analgesic Protection in Rats.
非偶然急性疼痛应激驱动大鼠镇痛保护。
  • 批准号:
    575854-2022
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
    Alexander Graham Bell Canada Graduate Scholarships - Master's
Prefrontal Cortex Hemodynamic Responses to Mindfulness Meditation and Acute Pain
前额皮质血流动力学对正念冥想和急性疼痛的反应
  • 批准号:
    467076
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
    Studentship Programs
A Multimodal Approach for Monitoring Prolonged Acute Pain in Neonates
监测新生儿长期急性疼痛的多模式方法
  • 批准号:
    9979265
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Endocannabinoid Metabolism in Acute Pain
急性疼痛中的内源性大麻素代谢
  • 批准号:
    10356880
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
A Multimodal Approach for Monitoring Prolonged Acute Pain in Neonates
监测新生儿长期急性疼痛的多模式方法
  • 批准号:
    10218273
  • 财政年份:
    2020
  • 资助金额:
    --
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