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: 8705050
• 负责人: CLIFFORD J WOOLF
• 金额: $ 26.78万
• 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/8705050
• 关键词: 4 hydroxynonenal; Ablation; Acute; Acute Pain; Address; Adopted; Afferent Neurons; Afferent Pathways; Agonist; Analgesics; Animals; Arthritis; Atopic Dermatitis; Axon; Behavioral; Body Temperature; Calcium Channel Blockers; Capsaicin; Cells; Charge; Chemicals; Chronic; Collaborations; Data; Genetic; Glutamates; Heating; Inflammation; Inflammatory; Instruction; Ion Channel; Label; Lidocaine; Lipids; Local anesthesia; Mechanics; Mediating; Modality; Modeling; Mus; Nerve; Neurons; Nociception; Nociceptors; Pain; Pain management; Pathway interactions; Peripheral; Protons; Rattus; Role; Side; Sodium; Sodium Channel Blockers; Stimulus; Synaptic Transmission; System; TRP channel; TRPV1 gene; Testing; Therapeutic; Variant; Vesicle; Work; bean; behavior measurement; chronic pain; design; in vivo; inflammatory neuropathic pain; ion channel blocker; keratinocyte; mustard oil; nerve injury; neuromechanism; novel strategies; novel therapeutic intervention; pain behavior; pain inhibition; painful neuropathy; patch clamp; programs; response; soft tissue; targeted delivery

The specific contribution of different primary sensory neurons in producing pain and itch will be investigated by targeted delivery of an impermeant cationic sodium channel blocker (QX-314, a quaternary derivative of lidocaine) through large-pore ion channels differentially expressed on afferents. The aim is to electrically silence subsets of axons using combinations 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 lasting "pain-specific" local anesthesia, and our pilot data suggest that TRPA1 and P2X3 activation 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 functional effects on nociception of blocking TRPV1, TRPA1 and P2X3 expressing nociceptors in naive rats and mice, measuring behavioral deficits in response to specific mechanical, thermal and chemical stimuli. The afferent silencing strategy will also be used to identify 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 constitutively activated by endogenous agonists during peripheral inflammation, 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 inflammation but not in naive animals. We will now explore if QX314 administered to peripheral terminals or nerves alters different modalities of pain sensitivity in soft tissue, incisional, arthritic, and peripheral neuritic inflammatory models, as well as in neuropathic pain and pruritic atopic dermatitis models. These strategies will help both identify the cellular mechanisms of nociceptive, inflammatory and neuropathic pain, acute and chronic itch and develop opportunities for targeted novel therapeutic interventions to treat these conditions.

不同的原发性感觉神经元在产生疼痛和瘙痒中的特定贡献将通过针对通过大孔离子通道的大孔离子通道（QX-314，QX-314，QX-314，QX-314，QX-314，QX-314，QX-314，QX-314，QX-314）进行研究。目的是使用QX-314和大孔离子通道激动剂的组合将轴突的电沉降子集进行电沉降。我们已经验证了使用辣椒素和QX-314表达TRPV1表达伤害感受器的策略，以产生持久的“疼痛特异性”局部麻醉，而我们的试验数据表明，TRPA1和P2X3激活的芥末油和ATP还允许QX-314 Perp to drg神经元进入DRG神经元。我们将使用DRG神经元中的全细胞贴片夹记录确认这一点。然后，该策略将在体内使用，以确定在幼稚大鼠和小鼠中表达伤害感受器的阻塞TRPV1，TRPA1和P2X3的功能作用，以响应特定的机械，热和化学刺激来测量行为缺陷。传入的沉默策略还将用于确定哪些大孔离子通道表达主要传入剂有助于组胺能和非 - 抗蛋白能瘙痒。仅施用QX-314后的沉默传入的存在将用于确定在周围炎症，神经损伤，急性和慢性瘙痒之后的内源性激动剂，急性和慢性瘙痒，何时以及哪里。我们的试点数据表明，QX-314在炎症存在下阻止了伤害感受器末端，但在幼稚的动物中却没有阻止。现在，我们将探讨QX314是否施用到周围末端或神经会改变软组织，切开，关节炎，关节炎和周围神经炎症模型以及神经性疼痛以及神经性疼痛和PRURITIC性皮肤病模型的不同方式。这些策略将有助于确定伤害性，炎症性和神经性疼痛，急性和慢性瘙痒的细胞机制，并为有针对性的新型治疗干预措施开发机会来治疗这些疾病。