Targeted Pharmacological Silencing of Sensory Neurons to Inhibit Pain and Itch

靶向药物沉默感觉神经元以抑制疼痛和瘙痒

• 批准号: 8377996
• 负责人: CLIFFORD J WOOLF
• 金额: $ 28.15万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8377996
• 关键词: 4 hydroxynonenal; Ablation; Acute; Acute Pain; Address; Adopted; Afferent Neurons; Afferent Pathways; Agonist; Analgesics; Animals; Atopic Dermatitis; Axon; Behavioral; Body Temperature; Calcium Channel Blockers; Capsaicin; Cells; Charge; Chemicals; Chronic; Data; Genetic; Glutamates; Heating; Inflammation; Inflammatory; Ion Channel; Label; Lidocaine; Lipids; Local anesthesia; Mechanics; Mediating; Modeling; Mus; Nerve; Neurons; Nociception; Nociceptors; Pain; Pain management; Pathway interactions; Peripheral; Principal Investigator; Protons; Rattus; Role; Side; Sodium; Sodium Channel Blockers; Stimulus; Synaptic Transmission; System; TRP channel; TRPV1 gene; Testing; The Sun; Therapeutic; Variant; Vesicle; Work; bean; behavior measurement; chronic pain; design; in vivo; inflammatory neuropathic pain; ion channel blocker; mustard oil; nerve injury; neuromechanism; novel strategies; novel therapeutic intervention; novel therapeutics; pain behavior; pain inhibition; painful neuropathy; patch clamp; programs; response; targeted delivery; transmission process

The specific contribufion of different primary sensory neurons in producing pain and itch will be invesfigated by targeted delivery of an impermeant cafionic sodium channel blocker (QX-314, a quaternary derivative of lidocaine) through large-pore ion channels differenfially expressed on afferents. The aim is to electrically silence subsets of axons using combinafions of QX-314 and large-pore ion channel agonists. We have validated this strategy for TRPV1-expressing nociceptors using capsaicin and QX-314 to produce a long lasfing "pain-specific" local anesthesia, and our pilot data suggest that TRPAl and P2X3 activafion by mustard oil and ATP also allow QX-314 permeation into DRG neurons. We will confirm this using whole cell patch clamp recordings in DRG neurons. The strategy will then be used in vivo to determine the funcfional effects on nociception of blocking TRPVl, TRPAl and P2X3 expressing nociceptors in naive rats and mice, measuring behavioral deficits in response to speciflc mechanical, thermal and chemical sfimuli. The afferent silencing strategy will also be used to idenfify which large-pore ion channel expressing primary afferents contribute to histaminergic and non-histaminergic itch. The presence of silenced afferents after administering QX-314 alone will be used to establish if large-pore ion channels are consfitufively acfivated by endogenous agonists during peripheral inflammafion, after nerve injury, in acute and chronic itch, when, and where. Our pilot data show that QX-314 blocks nociceptor terminals in the presence of inflammafion but not in naive animals. We will now explore if QX314 administered to peripheral terminals or nerves alters different modalifies of pain sensitivity in soft fissue, incisional, arthrific, and peripheral neuritic inflammatory models, as well as in neuropathic pain and pruritic atopic dermafitis models. These strategies will help both identify the cellular mechanisms of nocicepfive, inflammatory and neuropathic pain, acute and chronic itch and develop opportunifies for targeted novel therapeutic interventions to treat these condifions. RELEV/VNCE (See instmctions): We propose to develop a new analgesic strategy; targeting the pain pathway in the periphery using large- pore lon channels specific to the system as a means of delivering a sodium channel blocker only into defined sets of neurons. The proposal will test the potential of this appraoch for acute and chronic pain therapy.

不同的主要感觉神经元在产生疼痛和瘙痒时的特定贡献将被侵入 通过针对无形的咖啡馆钠通道阻滞剂的靶向输送（QX-314，第四纪衍生物的 利多卡因）通过传入的大孔离子通道不同表达的大孔离子通道。目的是电气 使用QX-314和大孔离子通道激动剂的组合的轴突沉默子集。我们有 使用辣椒素和QX-314验证了对TRPV1表达伤害感受器的策略 LASFING“疼痛特异性”局部麻醉，我们的试点数据表明TRPAL和P2X3 Activafion通过 芥末油和ATP还允许QX-314渗透到DRG神经元中。我们将使用整个单元格确认这一点 DRG神经元中的斑块夹记录。然后将在体内使用该策略来确定函数 在幼稚大鼠和小鼠中表达伤害感受器的阻塞TRPVL，TRPAL和P2X3的伤害感受的影响， 响应于指定机械，热和化学SFIMULI的响应行为缺陷。传入 沉默策略还将用于鉴定出哪些大孔离子通道表达主要传入 有助于组胺能和非速激素能瘙痒。管理后存在沉默的传入 仅QX-314将用于确定大孔离子通道是否被内源性助长了 周围炎症期间的激动剂，神经损伤后，急性和慢性瘙痒，何时何地。我们的 试点数据显示，QX-314在炎症存在下阻止了伤害感受器终端 动物。现在，我们将探讨QX314是否用于外围终端或神经会改变不同的 在软裂隙，切口，关节和周围神经炎性模型中疼痛敏感性的模态， 以及神经性疼痛和核性皮肤皮肤病模型。这些策略将有助于确定 鼻孔，炎症和神经性疼痛，急性和慢性瘙痒的细胞机制 为有针对性的新型治疗干预措施开发机会来治疗这些条件。 相关/vnce（请参阅Instmctions）： 我们建议制定一种新的镇痛策略；使用大型靶向周围的疼痛途径 孔隆通道特定于系统，作为将钠通道阻滞剂传递到定义的手段 一组神经元。该提案将测试此评估的急性和慢性疼痛疗法的潜力。