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
• 负责人: BRUCE P BEAN
• 金额: $ 37.06万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/7729878
• 关键词: Action Potentials; Address; Adult; Afferent Neurons; Affinity; Agonist; Aminacrine; Amitriptyline; Anesthetics; Autonomic Nerve Block; Behavioral; Binding; Capsaicin; Cations; Cell membrane; Cells; Charge; Childbirth; Chronic; Clinical Treatment; Conduction Anesthesia; Data; Dental Care; Development; Epidural Anesthesia; Fiber; Flecainide; Generations; Goals; Lead; Lidocaine; Local Anesthetics; Local anesthesia; Measures; Minor Surgical Procedures; Motor; Nature; Neurons; Nociception; Nociceptors; Operative Surgical Procedures; Pain; Paralysed; Permeability; Pharmaceutical Preparations; Population; Protein Kinase C; Rattus; Relative (related person); Research; Resistance; Signal Transduction; Site; Sodium Channel; Sodium Channel Blockers; Spinal Ganglia; TRPV1 gene; Testing; Thoracic Surgical Procedures; Time; Unconscious State; base; chronic neuropathic pain; depressed; expression cloning; improved; patch clamp; public health relevance; research study; voltage

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）：疼痛是由特定的原发性神经元群体中的动作电位发出信号，称为伤害感受器。局部麻醉药的给药提供了最有效的疼痛缓解形式而不会丧失意识，这些麻醉是通过抑制电压依赖性钠通道的作用，从而降低了电兴奋性。临床上使用的局部麻醉是至少部分地存在于疏水，无负荷形式的部分，可以通过细胞膜进入神经元。这些麻醉剂在所有神经元（不仅是伤害感受器）中输入并抑制兴奋性，因此除了阻塞疼痛外，还可以产生许多不良影响（包括瘫痪和自主信号的阻滞）。拟议的研究是基于最近的发现，即钠通道阻断药物可以通过将Lidocaine（QX-314）永久性带电的衍生物与Capsaicin（TRPV1通道的激动剂）共同启用。提案中的初步数据支持的基本假设是，QX-314可以通过通过TRPV1通道形成的孔来输入伤害感受器。拟议的研究的总体目标是确定TRPV1激活剂和带电的钠通道阻滞剂的组合，以优化伤害性感觉神经元的兴奋性块。要解决的具体问题包括：有效进入带电钠通道阻滞剂的尺寸限制是多少？阻滞剂进入的时间过程如何取决于TRPV1激动剂的性质和浓度？可以通过激活蛋白激酶C来增强阻滞剂的进入和积累吗？是否有TRPV1激动剂可以允许QX-314进入而不先刺激动作电位发射？细胞内QX-314的相对效力是阻止已知对伤害感受器兴奋重要的不同类型的钠通道的相对效力？这些问题将在大鼠背根神经元中的天然TRPV1通道和钠通道上的斑块夹实验进行解决，并通过使用克隆的TRPV1通道的异源表达进行其他实验。这些机制的表征应促进基于带电的钠通道阻滞剂进入疼痛感应神经元的目标进入疼痛缓解的新临床治疗方法。这种治疗对于在分娩，手术和牙科手术以及某些形式的慢性神经源性疼痛的选择性缓解疼痛方面应具有很高的优势。公共卫生相关性：研究的目的是基于选择性靶向钠通道阻断药物对疼痛感应神经元的选择性靶向，以开发一种新的治疗方法。通过与Capsaicin（TRPV1通道的激动剂）共同涂抹一个永久带电的利多卡因衍生物，可以阻止疼痛感应神经元的电兴奋性，但不能阻止其他类型的神经元中的电动兴奋性，从而避免运动瘫痪和与常规局部局部局部局部发生的自主纤维块。除了允许特定疼痛的局部麻醉（例如，用于牙科手术和轻微手术）外，这可能会改善分娩和胸外科手术的硬膜外麻醉，并可能改善某些形式的慢性神经性疼痛的治疗方法。