Mechanisms in Primary Nociceptors that Drive Ongoing Activity and Ongoing Pain

驱动持续活动和持续疼痛的初级伤害感受器的机制

基本信息

批准号：
10611897
负责人：
EDGAR T. WALTERS
金额：
$ 42.3万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10611897
关键词：
Action Potentials Acute Acute Pain Afferent Neurons Analgesics Anesthesia procedures Attention Automobile Driving C Fiber Capsaicin Cells Chemosensitization Chronic Clinical Cyclic AMP Dependence Distress Dose Drug usage Electrophysiology (science)Fiber Forskolin Foundations Frequencies Freund&apos s Adjuvant Generations Hyperalgesia Inflammation Inflammatory Injections Intervention Investigation Ion Channel Ions Knowledge Link Mediator Medical Membrane Potentials Modeling Mus Nature Neurons Neuropathy Nociception Nociceptors Opioid Pain Pathway interactions Peripheral Persistent pain Pharmaceutical Preparations Potassium Channel Probability Procedures Property Rattus Reporting Resistance Rest Risk Role Serotonin Signal Transduction Spinal Ganglia Spinal cord injury Structure of trigeminal ganglion TRPV1 gene Testing Transgenic Mice Transgenic Organisms Translating allodynia behavior test chronic pain defined contribution economic cost effective therapy in vitro activity in vivo in vivo evaluation inhibitor novel pharmacologic pre-clinical prevent side effect social spinal nerve posterior root virtual voltage

项目摘要

Project Summary The long-term objective of this project is to discover novel, highly targeted approaches for treating ongoing pain by defining critical mechanisms of ongoing activity (OA) in primary nociceptors that drive this pain. Recent discoveries revealed that the OA generated spontaneously in probable nociceptors and linked to ongoing pain after spinal cord injury (SCI) is associated with all three electrophysiological alterations that, in principle, can promote OA. These are depolarization of resting membrane potential (RMP), reduced voltage threshold for action potentials (APs), and increased frequency of large, transient, depolarizing spontaneous fluctuations (DSFs). Two extrinsic mediators related to inflammation, serotonin (5-HT) and capsaicin (mimicking endogenous TRPV1 activators), also promote OA, in large part by enhancing DSFs. Virtually nothing is known about mechanisms underlying large DSFs. Three specific aims will test hypotheses about DSF generation and potentiation, employing whole cell patch recording, stimulation by Ca2+ uncaging, pharmacological and transgenic approaches, in vivo recording, and behavioral tests. Aim 1 will define ion conductance and cell signaling (Ca2+ and cAMP) contributions to the acute generation of large DSFs, taking advantage of the ability of 5-HT, forskolin, and capsaicin to rapidly stimulate large DSFs, using naïve rats and transgenic mice. The focus will include HCN channels, T-type Ca2+ channels, and Nav1.8 channels. Special attention will be paid to TRPC4/5 channels, which are important for OA and have unusual properties that account for unique features of large DSFs. Aim 2 will define ion conductances and cell signals that promote large DSF generation in chronic SCI and in a subacute peripheral inflammation model (hindpaw injection of complete Freund's adjuvant - CFA). The channels found in Aim 1 to be important for large DSFs will be tested for altered contributions and expression in each model. Alterations promoting OA are predicted to be shared in these models (and thus to potentially drive many forms of ongoing pain). Aim 3 will test the prediction that combined interventions selectively blocking large DSFs and elevating AP threshold will reduce ongoing pain. A novel analgesic strategy will be tested, which combines a drug that prevents large DSF generation (a TRPC4/5 blocker) with a drug that selectively elevates AP threshold in nociceptors (a Nav1.8 blocker). The combination should efficiently suppress nociceptor OA and consequent ongoing pain at doses lower than required to observe any effect on ongoing pain from either drug alone. This prediction will be tested in vivo both on C-fiber OA recorded from dorsal roots of anesthetized rats and on ongoing pain in SCI rats and in rat and mouse CFA models. This targeted approach could lay the foundation for new treatments for severe ongoing pain that have relatively few side effects and provide an alternative to opioids, with their attendant risks.

项目概要该项目的长期目标是发现新颖的、高度针对性的方法来治疗持续的通过定义导致这种疼痛的主要伤害感受器持续活动（OA）的关键机制来减轻疼痛。研究发现，OA 在可能的伤害感受器中自发产生，并与持续的疼痛有关脊髓损伤（SCI）后与所有三种电生理改变相关，原则上，这些是静息膜电位 (RMP) 的去极化、降低的电压阈值。动作电位 (AP) 以及大的、瞬时的、去极化自发波动的频率增加（DSF）与炎症相关的两种外在介质，血清素（5-HT）和辣椒素（模仿）。内源性 TRPV1 激活剂）也能促进 OA，很大程度上是通过增强 DSF 来实现的，但实际上对此一无所知。关于大型 DSF 背后的机制的三个具体目标将测试有关 DSF 生成和的假设。增强作用，采用全细胞贴片记录，Ca2+解笼锁刺激，药理学和转基因方法、体内记录和行为测试将定义离子电导和细胞。信号传导（Ca2+ 和 cAMP）对大 DSF 的急性产生有贡献，利用这种能力使用幼稚大鼠和转基因小鼠，使用 5-HT、毛喉素和辣椒素快速刺激大 DSF。重点包括HCN通道、T型Ca2+通道和Nav1.8通道。 TRPC4/5 通道，对于 OA 很重要，并且具有不寻常的属性，可以实现独特的功能目标 2 将定义促进大 DSF 生成的离子电导和细胞信号。慢性 SCI 和亚急性周围炎症模型（后爪注射完全弗氏佐剂 - CFA）。目标 1 中发现的对大型 DSF 很重要的渠道将进行更改贡献和测试。预测促进 OA 的改变在这些模型中是共享的（因此目标 3 将测试结合干预措施的预测选择性阻断大 DSF 并提高 AP 阈值将减轻持续疼痛。将测试策略，该策略将防止大量 DSF 生成的药物（TRPC4/5 阻滞剂）与选择性提高伤害感受器 AP 阈值的药物（Nav1.8 阻滞剂）。有效抑制伤害感受器 OA 和随之而来的持续疼痛，剂量低于观察任何情况所需的剂量单独使用任一药物对持续疼痛的影响将在记录的 C 纤维 OA 上进行体内测试。来自麻醉大鼠的背根以及 SCI 大鼠以及大鼠和小鼠 CFA 模型的持续疼痛。有针对性的方法可以为治疗严重持续性疼痛的新疗法奠定基础，而这种疗法相对较少副作用并提供阿片类药物的替代品，及其伴随的风险。