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
• 负责人: BRUCE P BEAN
• 金额: $ 36.34万
• 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 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8290395
• 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; abstracting; base; chronic neuropathic pain; expression cloning; improved; patch clamp; research study; voltage

Project Summary/ Abstract 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.

项目概要/摘要 疼痛是通过特定初级感觉神经元群中动作电位的产生来发出信号的 称为伤害感受器。在不丧失意识的情况下缓解疼痛的最有效形式是 局部麻醉药的施用，其作用是通过抑制电压依赖性钠通道和 从而抑制电兴奋性。临床上使用的局部麻醉剂是至少存在的分子 部分处于疏水性、不带电荷的形式，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，因此可以有许多 除了阻止疼痛之外，还会产生不良影响（包括麻痹和自主神经信号传导受阻）。 拟议的研究基于最近的一项发现，即钠通道阻断药物可以 通过共同应用永久带电的利多卡因衍生物（QX- 314) 与辣椒素（TRPV1 通道的激动剂）。基本假设得到以下支持 该提案中的初步数据是，QX-314可以通过毛孔进入伤害感受器 由 TRPV1 通道形成。拟议研究的总体目标是确定以下组合 TRPV1 激活剂和带电钠通道阻滞剂可优化对神经细胞兴奋性的阻滞 伤害性感觉神经元。要解决的具体问题包括： 的大小限制是多少？ 带电钠通道阻滞剂的有效进入？拦截器进入的时间进程如何取决于 TRPV1 激动剂的性质和浓度？能否增强阻滞剂的进入和积累 通过激活蛋白激酶C？是否有 TRPV1 激动剂允许 QX-314 无需先进入 刺激动作电位的放电？细胞内 QX-314 阻断的相对效力是多少？ 已知对伤害感受器的兴奋性很重要的不同类型的钠通道？ 这些问题将通过对天然 TRPV1 通道进行膜片钳实验来解决 大鼠背根神经节神经元的钠通道，并使用异源进行额外的实验 克隆的 TRPV1 通道的表达。表征这些机制应有助于 基于带电钠的靶向进入开发新的临床缓解疼痛疗法 通道阻滞剂进入痛觉神经元。这样的治疗对于更多人来说应该是非常有利的 选择性缓解分娩、手术和牙科手术中的疼痛，也可能缓解某些形式的慢性疼痛 神经源性疼痛。

项目成果

Selectively targeting pain in the trigeminal system.

• DOI: 10.1016/j.pain.2010.02.016
• 发表时间: 2010-07
• 期刊: Pain
• 影响因子: 7.4
• 作者: Kim HY;Kim K;Li HY;Chung G;Park CK;Kim JS;Jung SJ;Lee MK;Ahn DK;Hwang SJ;Kang Y;Binshtok AM;Bean BP;Woolf CJ;Oh SB
• 通讯作者: Oh SB

Functional properties and toxin pharmacology of a dorsal root ganglion sodium channel viewed through its voltage sensors.

• DOI: 10.1085/jgp.201110614
• 发表时间: 2011-07
• 期刊: The Journal of general physiology
• 作者: Bosmans F;Puopolo M;Martin-Eauclaire MF;Bean BP;Swartz KJ
• 通讯作者: Swartz KJ