TRP Channel Mediated Pain Circuitry

描述(申请人提供)：这项修订后的PO1提案的基本目标是了解疼痛和瘙痒是如何由不同的伤害感受器和瘙痒感受器感觉神经元产生的，并开发能够在药物上沉默相关信号的技术，作为一种潜在的新治疗策略。该计划现在完全集中在外周神经系统和瞬时受体电位(Trp)TRPV1、TRPA1和TRPV3通道以及P2X嘌呤能配体门控离子通道上，这两个通道都是处理感觉信号的关键元素，更是因为它们都是允许药物分子渗透到神经细胞内部以阻止兴奋和递质释放的大孔道。Clifford Woolf在项目1中将通过通过通道输送永久带电的钠通道阻滞剂QX-314后，通过瞬时沉默轴突来识别表达疼痛和瘙痒的初级感觉神经元的不同TRPV11、TRPV3、TRPA1和P2X3亚组的功能。在项目2中，Bruce Bean还将探索如何通过Trp和嘌呤能配体门控离子通道渗透药物来沉默初级感觉神经元，但通过传递阳离子钙通道阻滞剂来扰乱外周的囊泡释放以减少神经源性炎症和在脊髓中消除突触传递。David Clapham的项目3将确定TRPV3如何以及在哪里导致疼痛和瘙痒(在角质形成细胞或感觉神经元中)，这是一个重要的问题，因为TRPV3拮抗剂在临床前模型中是止痛药，即将进行临床测试，还将探索离子通道阻滞剂通过TRPV3的渗透是否可以用于改变角质形成细胞和初级感觉神经元对疼痛和瘙痒的贡献。在项目4中，马秋福将使用基因技术来沉默已定义的初级感觉神经元，以梳理出它们在疼痛和瘙痒中的特定作用。一种初级感觉神经元SP

DESCRIPTION (provided by applicant): The fundamental goal of this revised PO1 proposal is to understand how pain and itch are generated by different nociceptor and pruriceptors sensory neurons and to develop techniques that can pharmacologically silence the signals responsible, as a potential novel therapeutic strategy. The program is now entirely focused on the peripheral nervous system and on the Transient Receptor Potential (TRP) TRPV1, TRPA1 and TRPV3 channels and P2X purinergic ligand-gated ion channels, both because they are key elements in the processing of sensory signals, and even more so because they are all large pore channels allowing permeation of drug molecules into the interior of nerve cells to block excitation and transmitter release. Clifford Woolf in Project 1 will identify the function of the different subsets of TRPV1l, TRPV3, TRPA1 and P2X3 expressing primary sensory neurons in pain and itch by transiently silencing their axons after delivery of the permanently charged sodium channel blocker QX-314 through the channels. Bruce Bean in Project 2 will also explore how permeation of drugs through TRP and purinergic ligand-gated ion channels can be used to silence primary sensory neurons, but by using delivery of cationic calcium channel blockers to disrupt vesicle release in the periphery to reduce neurogenic inflammation and in the spinal cord to eliminate synaptic transmission. David Clapham's Project 3 will identify how and where TRPV3 contributes to pain and itch (in keratinocytes or sensory neurons), an important issue since TRPV3 antagonists are analgesic in preclinical models and are about to be tested clinically, and will also explore if permeation of ion channel blockers through TRPV3 can be used to modify the contribution of keratinocytes and primary sensory neurons to pain and itch. Qiufu Ma in Project 4 will use genetic techniques to silence defined primary sensory neurons to tease out their specific role in pain and itch. A primary sensory neuron sp