TRP Channel Mediated Pain Circuitry

描述（由申请人提供）：本修订后的PO1提案的基本目标是了解疼痛和瘙痒是如何由不同的痛觉感受器和痛觉感受器感觉神经元产生的，并开发可以在药理学上沉默相关信号的技术，作为一种潜在的新型治疗策略。该计划现在完全集中于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，这两者都是因为它们是处理感觉信号的关键要素，更重要的是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通道。项目1中的Clifford Woolf将通过通道递送永久带电的钠通道阻阻剂QX-314后，通过短暂沉默轴突，确定表达初级感觉神经元的TRPV1l、TRPV3、TRPA1和P2X3不同亚群在疼痛和瘙痒中的功能。Bruce Bean在Project 2中也将探索如何通过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，但通过使用阳离子钙通道阻阻剂来破坏外周的囊泡释放，以减少神经源性炎症，并在脊髓中消除突触传递。David Clapham的Project 3将确定TRPV3如何以及在何处促进疼痛和瘙痒（在角化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具有镇痛作用，即将进行临床测试，并且还将探索离子通道阻断剂通过TRPV3的渗透是否可以用来改变角化细胞和初级感觉神经元对疼痛和瘙痒的贡献。项目4的马秋富将使用基因技术沉默确定的初级感觉神经元，以梳理出它们在疼痛和瘙痒中的具体作用。初级感觉神经元

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