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

基本信息

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
项目类别：
财政年份：
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

项目摘要

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.

将通过传入神经上差异表达的大孔离子通道靶向递送非渗透性阳离子钠通道阻滞剂（QX-314，利多卡因的四元衍生物）来研究不同初级感觉神经元在产生疼痛和瘙痒中的具体贡献。目的是使用 QX-314 和大孔离子通道激动剂的组合来电沉默轴突子集。我们已经使用辣椒素和 QX-314 验证了表达 TRPV1 的伤害感受器的这一策略，以产生持久的“疼痛特异性”局部麻醉，并且我们的试验数据表明芥子油和 ATP 激活 TRPA1 和 P2X3 也允许 QX-314 渗透进入 DRG 神经元。我们将使用 DRG 神经元中的全细胞膜片钳记录来证实这一点。然后，该策略将在体内用于确定阻断幼稚大鼠和小鼠中表达伤害感受器的TRPV1、TRPA1和P2X3对伤害感受的功能影响，测量对特定机械、热和化学刺激的反应行为缺陷。传入沉默策略还将用于识别哪些表达初级传入的大孔离子通道导致组胺能和非组胺能瘙痒。单独施用 QX-314 后存在的沉默传入神经将用于确定大孔离子通道是否在外周炎症期间、神经损伤后、急性和慢性瘙痒、何时何地被内源性激动剂组成性激活。我们的试验数据显示，QX-314 在存在炎症的情况下阻断伤害感受器末梢，但在幼稚动物中则不然。我们现在将探讨外周末梢或神经施用 QX314 是否会改变软组织、切口、关节炎和外周神经炎炎症模型以及神经性疼痛和瘙痒性特应性皮炎模型中的不同疼痛敏感性模式。这些策略将有助于识别伤害性疼痛、炎症性疼痛和神经性疼痛、急性和慢性瘙痒的细胞机制，并为治疗这些疾病的有针对性的新型治疗干预措施创造机会。