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
• 负责人: BRUCE P BEAN
• 金额: $ 8.48万
• 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/8119847
• 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; Depressed mood; 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; 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）：疼痛是通过称为伤害感受器的特定初级感觉神经元群中产生动作电位来发出信号的。在不丧失意识的情况下缓解疼痛的最有效形式是使用局部麻醉剂，其作用是抑制电压依赖性钠通道，从而抑制电兴奋性。临床上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，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，因此除了阻止疼痛之外，还可能产生许多不良影响（包括麻痹和自主神经信号传导阻断）。拟议的研究基于最近的一项发现，即通过共同应用永久带电的利多卡因衍生物 (QX-314) 和辣椒素（TRPV1 通道的激动剂），钠通道阻断药物可以选择性地靶向伤害感受器。提案中初步数据支持的基本假设是，QX-314 可以通过 TRPV1 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 TRPV1 激活剂和带电钠通道阻滞剂的组合，以优化对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尺寸限制是多少？ TRPV1 激动剂的性质和浓度如何影响阻滞剂进入的时间进程？蛋白激酶 C 的激活能否增强阻断剂的进入和积累？是否有 TRPV1 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很重要的不同类型钠通道的相对效力是多少？这些问题将通过对大鼠背根神经节神经元的天然 TRPV1 通道和钠通道进行膜片钳实验以及使用克隆的 TRPV1 通道的异源表达进行额外的实验来解决。表征这些机制应有助于基于带电钠通道阻滞剂靶向进入疼痛感知神经元的新的临床缓解疼痛疗法的开发。此类治疗对于分娩、手术和牙科手术中更有选择性的疼痛缓解以及可能对某些形式的慢性神经源性疼痛非常有利。公共健康相关性：该研究的目标是开发一种基于钠通道阻断药物选择性靶向疼痛感知神经元的新疼痛治疗方法。通过将永久带电的利多卡因衍生物与TRPV1通道激动剂辣椒素共同应用，可以阻断痛觉神经元的电兴奋性，但不能阻断其他类型神经元的电兴奋性，从而避免发生运动麻痹和自主神经纤维阻断与传统的局部麻醉。除了允许针对疼痛的局部麻醉（例如牙科手术和小型手术）之外，这可能会改善分娩和胸外科手术中的硬膜外麻醉，并可能改善某些形式的慢性神经性疼痛的治疗。