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

• 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
• 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' 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

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.

项目摘要 该项目的长期目标是发现用于治疗正在进行的新颖，高度针对性的方法 通过定义促进这种疼痛的主要伤害感受器中持续活动（OA）的关键机制（OA）来疼痛。最近的 发现揭示了OA在可能的伤害感受器中赞成生成，并与持续的疼痛有关 脊髓损伤后（SCI）与所有三种电生理改变有关，原则上可以 促进OA。这些是静息膜电位（RMP）的沉积，降低了电压阈值 动作电位（AP），并增加大型，瞬态，分裂的赞助波动的频率 （DSF）。两个与炎症，5-羟色胺（5-HT）和辣椒素有关的外部介质（模仿） 内源性TRPV1激活剂），也很大程度上通过增强DSF来促进OA。几乎什么都没知道 关于大型DSF的基础机制。三个具体目标将检验有关DSF生成和的假设 增强，采用全细胞贴片记录，CA2+渗透刺激，药物和药物刺激 转基因方法，体内记录和行为测试。 AIM 1将定义离子电导和电池 信号传导（CA2+和CAMP）对大型DSF的急性产生的贡献，利用能力 使用幼稚的大鼠和转基因小鼠的5-HT，Forskolin和辣椒素迅速刺激大型DSF。 焦点将包括HCN通道，T型CA2+通道和NAV1.8通道。特别关注 TRPC4/5频道，对OA很重要，并且具有不寻常的特性，可以说明独特的功能 大型DSF。 AIM 2将定义离子电导和细胞信号，以促进大型DSF生成 慢性SCI和亚急性外围注射模型（印度河注入完整的弗朗德的可调 -CFA）。 AIM 1中发现的渠道对于大型DSF很重要，将测试改变的贡献和 在每个模型中的表达。预计促进OA的改变将在这些模型中共享（因此 潜在地驱动许多形式的持续疼痛）。 AIM 3将测试合并干预措施的预测 有选择地阻止大型DSF和提高AP阈值将减轻持续的疼痛。一种新颖的镇痛药 将测试策略，该策略结合了一种可以防止大型DSF生成（TRPC4/5阻滞剂）和A的药物 有选择地提高伤害感受器AP阈值的药物（NAV1.8阻滞剂）。组合应该 有效地抑制伤害感受器OA，并以比观察到任何观察的剂量低于剂量的持续疼痛 仅任何两种药物就会持续疼痛。该预测将在记录的C纤维OA上在体内进行测试 从麻醉大鼠的背部根部和大鼠和小鼠CFA模型中持续的疼痛。这 有针对性的方法可以为严重持续疼痛的新疗法奠定基础 副作用，并提供替代烯烃的替代风险。