Selective targeting of sodium channel blockers to pain-sensing neurons

钠通道阻滞剂选择性靶向痛觉神经元

基本信息

  • 批准号:
    8068184
  • 负责人:
  • 金额:
    $ 36.34万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-05-01 至 2013-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Pain is signaled by generation of action potentials in a specific population of primary sensory neurons known as nociceptors. The most effective form of pain relief without loss of consciousness is provided by administration of local anesthetics, which act by inhibiting voltage-dependent sodium channels and thereby depressing electrical excitability. Clinically-used local anesthetics are molecules that exist at least partially in a hydrophobic, uncharged form that can enter neurons through the cell membrane. These anesthetics enter and inhibit excitability in all neurons, not just nociceptors, and thus can have many undesirable effects (including paralysis and block of autonomic signaling) in addition to blocking pain. The proposed research is based on a recent finding that sodium channel blocking drugs can be targeted selectively to nociceptors by co-applying a permanently charged derivative of lidocaine (QX- 314) with capsaicin, an agonist for TRPV1 channels. The underlying hypothesis, supported by the preliminary data in the proposal, is that QX-314 can enter nociceptors by passing through the pore formed by TRPV1 channels. The overall goal of the proposed research is to identify combinations of TRPV1 activators and charged sodium channel blockers that optimize the block of excitability of nociceptive sensory neurons. Specific questions to be addressed include: What is the size limit for effective entry of charged sodium channel blockers? How does the time course of blocker entry depend on the nature and concentration of the TRPV1 agonist? Can blocker entry and accumulation be enhanced by activation of protein kinase C? Are there TRPV1 agonists that allow QX-314 entry without first stimulating firing of action potentials? What is the relative potency of intracellular QX-314 for blocking the different types of sodium channels known to be important for excitability of nociceptors? These questions will be addressed using patch clamp experiments on native TRPV1 channels and sodium channels in rat dorsal root ganglion neurons, with additional experiments using heterologous expression of cloned TRPV1 channels. Characterizing these mechanisms should facilitate the development of new clinical treatments for pain relief based on the targeted entry of charged sodium channel blockers into pain-sensing neurons. Such treatments should be highly advantageous for more selective pain relief in childbirth, surgery, and dental procedures and possibly for some forms of chronic neurogenic pain. PUBLIC HEALTH RELEVANCE: The goal of the research is to develop a new treatment for pain based on selective targeting of sodium channel blocking drugs to pain-sensing neurons. By co-applying a permanently charged lidocaine derivative with capsaicin, an agonist for TRPV1 channels, it is possible to block electrical excitability in pain-sensing neurons but not in other types of neurons, thus avoiding the motor paralysis and block of autonomic fibers that occurs with conventional local anesthesia. Besides allowing pain-specific local anesthesia (e.g. for dental procedures and minor surgery), this may lead to improved epidural anesthesia in childbirth and thoracic surgery and possibly improved treatments for some forms of chronic neuropathic pain.
描述(由申请人提供):疼痛通过在称为伤害感受器的特定初级感觉神经元群体中产生动作电位来发出信号。最有效的止痛而不失去意识的形式是局部麻醉剂,其作用是抑制电压依赖性钠通道,从而抑制电兴奋性。临床使用的局部麻醉剂是至少部分以疏水、不带电形式存在的分子,其可以通过细胞膜进入神经元。这些麻醉剂进入并抑制所有神经元的兴奋性,而不仅仅是伤害感受器,因此除了阻断疼痛外,还可能产生许多不良影响(包括麻痹和自主信号传导阻滞)。这项拟议的研究是基于最近的一项发现,即钠通道阻断药物可以通过将利多卡因(QX- 314)的永久电荷衍生物与辣椒素(TRPV 1通道的激动剂)共同应用而选择性地靶向伤害感受器。该提案中的初步数据支持的基本假设是,QX-314可以通过TRPV 1通道形成的孔进入伤害感受器。拟议研究的总体目标是确定TRPV 1激活剂和带电钠通道阻滞剂的组合,以优化伤害性感觉神经元兴奋性的阻滞。需要解决的具体问题包括:带电钠通道阻滞剂有效进入的大小限制是什么?阻断剂进入的时间过程如何取决于TRPV 1激动剂的性质和浓度?蛋白激酶C的激活能否增强阻滞剂的进入和积累?是否有TRPV 1激动剂允许QX-314进入而不首先刺激动作电位的放电?细胞内QX-314阻断已知对伤害感受器兴奋性重要的不同类型钠通道的相对效价是多少?这些问题将解决使用膜片钳实验对本地TRPV 1通道和钠通道在大鼠背根神经节神经元,与其他实验使用异源表达克隆TRPV 1通道。这些机制的特点应有助于开发新的临床治疗疼痛缓解的基础上,有针对性地进入带电的钠通道阻滞剂进入疼痛感应神经元。这种治疗方法对于分娩、手术和牙科手术中更有选择性的疼痛缓解以及某些形式的慢性神经源性疼痛应该是非常有利的。公共卫生关系:该研究的目标是开发一种新的疼痛治疗方法,该方法基于选择性靶向钠通道阻断药物对疼痛感觉神经元的作用。通过将永久带电的利多卡因衍生物与辣椒素(一种TRPV 1通道激动剂)共同应用,可以阻断痛觉神经元的电兴奋性,但不会阻断其他类型神经元的电兴奋性,从而避免了传统局部麻醉中发生的运动麻痹和自主神经纤维阻滞。除了允许疼痛特异性局部麻醉(例如牙科手术和小手术),这可能会导致分娩和胸外科手术中的硬膜外麻醉改善,并可能改善某些形式的慢性神经性疼痛的治疗。

项目成果

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BRUCE P BEAN其他文献

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{{ truncateString('BRUCE P BEAN', 18)}}的其他基金

Ion Channel Pharmacology for Pain and Epilepsy
疼痛和癫痫的离子通道药理学
  • 批准号:
    10449483
  • 财政年份:
    2022
  • 资助金额:
    $ 36.34万
  • 项目类别:
Ion Channel Pharmacology for Pain and Epilepsy
疼痛和癫痫的离子通道药理学
  • 批准号:
    10615776
  • 财政年份:
    2022
  • 资助金额:
    $ 36.34万
  • 项目类别:
Voltage-dependent ion channels controlling firing patterns of central neurons
电压依赖性离子通道控制中枢神经元的放电模式
  • 批准号:
    10225152
  • 财政年份:
    2020
  • 资助金额:
    $ 36.34万
  • 项目类别:
State-dependent interaction of antiepileptic drugs with voltage-dependent sodium channels and differential regulation of excitatory and inhibitory central neurons
抗癫痫药物与电压依赖性钠通道的状态依赖性相互作用以及兴奋性和抑制性中枢神经元的差异调节
  • 批准号:
    10332723
  • 财政年份:
    2019
  • 资助金额:
    $ 36.34万
  • 项目类别:
TRP Channel Mediated Pain Circuitry
TRP 通道介导的疼痛回路
  • 批准号:
    8299023
  • 财政年份:
    2011
  • 资助金额:
    $ 36.34万
  • 项目类别:
TRP Channel Mediated Pain Circuitry
TRP 通道介导的疼痛回路
  • 批准号:
    8153242
  • 财政年份:
    2011
  • 资助金额:
    $ 36.34万
  • 项目类别:
TRP Channel Mediated Pain Circuitry
TRP 通道介导的疼痛回路
  • 批准号:
    8541064
  • 财政年份:
    2011
  • 资助金额:
    $ 36.34万
  • 项目类别:
Selective targeting of sodium channel blockers to pain-sensing neurons
钠通道阻滞剂选择性靶向痛觉神经元
  • 批准号:
    8290395
  • 财政年份:
    2009
  • 资助金额:
    $ 36.34万
  • 项目类别:
Selective targeting of sodium channel blockers to pain-sensing neurons
钠通道阻滞剂选择性靶向痛觉神经元
  • 批准号:
    7729878
  • 财政年份:
    2009
  • 资助金额:
    $ 36.34万
  • 项目类别:
Selective targeting of sodium channel blockers to pain-sensing neurons
钠通道阻滞剂选择性靶向痛觉神经元
  • 批准号:
    8119847
  • 财政年份:
    2009
  • 资助金额:
    $ 36.34万
  • 项目类别:

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