Characterization of the Properties and Mechanisms of Photobiomodulation-Induced Axonal Block and Evaluation as a Treatment for Neuropathic Pain

光生物调节诱导的轴突阻滞的特性和机制的表征以及作为神经性疼痛治疗方法的评估

• 批准号: 10184296
• 负责人: Juanita J Anders
• 金额: $ 56.91万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10184296
• 关键词: Action Potentials; Acute; Address; Affect; American; Analgesics; Animals; Axon; Biological; Chronic; Clinic; Clinical; Computer Models; Confocal Microscopy; Data; Dependence; Development; Device Designs; Devices; Dose; Electron Microscopy; Elements; Evaluation; Eye; Family suidae; Fiber; Foundations; Goals; Health; Heating; Hour; Human; Image; Intervention; Investigation; Light; Literature; Longitudinal Studies; Microtubules; Miniature Swine; Modeling; Nerve; Nerve Block; Neuritis; Neurons; Nociception; Operative Surgical Procedures; Opioid; Pain; Patients; Peripheral Nerves; Pharmacology; Physiological; Pilot Projects; Pre-Clinical Model; Preparation; Property; Radiofrequency Interstitial Ablation; Randomized Controlled Trials; Rattus; Reporting; Research; Research Activity; Rodent; Rodent Model; Role; Societies; Source; Spinal Ganglia; Spottings; Structure; Synaptic Transmission; Syndrome; System; Techniques; Technology; Therapeutic; Time; Tissues; Translations; United States; Varicosity; Work; animal pain; base; behavior test; chronic pain; direct application; experience; first-in-human; implantable device; in vivo; insight; interest; neurotransmission; nociceptive response; opioid overdose; pain model; pain reduction; pain relief; painful neuropathy; photobiomodulation; pre-clinical; preclinical development; preclinical evaluation; preclinical study; prototype; relating to nervous system; response; sciatic nerve; standard of care; tool; transmission process; wound healing

Project Summary / Abstract Recent research indicates that when ~808 to 830 nm light is applied in immediate juxtaposition to target neurons or axons (within mm) through invasive techniques, C and Aδ fibers that convey pain-related information can temporarily and reversibly be “turned off” without affecting the functionality of the larger A fibers. If further developed, this photobiomodulation (PBM) effect has exciting possibilities as an implantable device-based treatment for various chronic pain syndromes, including neuropathic pains. This project takes important steps to develop fundamental and mechanistic understanding, and to provide a foundation for translation. In terms of fundamental and mechanistic understanding – first, the effect of PBM dose and wavelength on axonal block (in an ex vivo peripheral nerve preparation) and nociceptive response (in an in vivo rodent pain model) will be rigorously characterized. These data will provide important mechanistic insight and translational value. Second, the role of observed microtubule destabilization and the resulting axonal varicosities will be explored as contributors to the mechanism of the independently-observed action potential block. We will determine whether or not there is a correlation between effect size (functional data) and degree of microtubule instability (confocal microscopy and electron microscopy data). Computational models will be used to evaluate the effect of axonal varicosities on action potential propagation. Finally, the effect of pharmacological microtubule (de)stabilizers on PAB dose will be assessed. In terms of translational activities – the project includes development of pre-clinical-grade systems that allow PBM at the nerve to be applied chronically with the ultimate goal of demonstrating that chronic PBM can provide a persistent and profound analgesic effect in a large animal pain model (porcine). A fully implantable system based on an existing commercial neurostimulator will enable PBM to be delivered over extended periods of time. A percutaneous system will require repeated interventions over time (e.g., weekly interventions on the order of minutes), but will enable use of higher peak powers not achievable with the fully implantable system. The systems will be used in a porcine pain model (peripheral neuritis) that better mimicked the human response to pharmacological interventions than rodent models have been able to do. The pre-clinical studies will include a 30-day pilot study followed by a 6-month study in minipigs. In summary, this project will expand fundamental understanding of PBM-induced axonal block with an eye toward translational devices suitable for the treatment of chronic pain.

项目摘要 /摘要 最近的研究表明，当〜808至830 nm的光被立即并置以靶向神经元时 或通过侵入性技术，传达与疼痛相关信息的C和Aδ纤维可以 暂时和可逆地被“关闭”，而不会影响较大的A纤维的功能。如果进一步 开发的，这种光生物调节（PBM）效应具有令人兴奋的可能性 各种慢性疼痛综合征的治疗，包括神经性疼痛。该项目采取重要步骤 发展基本和机械的理解，并为翻译提供基础。 就基本和机械理解而言 - 首先，PBM剂量和波长对 轴突块（在体内外周神经制剂中）和伤害感受反应（在体内啮齿动物疼痛中 模型）将是严格的特征。这些数据将提供重要的机械洞察力和翻译 价值。其次，观察到的微管破坏稳定的作用和由此产生的轴突静脉曲张将是 探索是独立观察到的动作电势块机制的贡献者。我们将 确定效应大小（功能数据）和微管程度之间是否存在相关性 不稳定性（共聚焦显微镜和电子显微镜数据）。计算模型将用于评估 轴突静脉曲张对动作电势传播的影响。最后，药物微管的作用 （DE）将评估PAB剂量的稳定剂。 在翻译活动方面 - 项目包括开发临床前级系统，允许 pBM在神经处长期应用，其最终目标是证明慢性PBM可以提供 在大型动物疼痛模型（猪）中持久而深刻的镇痛作用。完全植入的系统 基于现有的商业神经刺激器，将使PBM在长时间内交付。 经皮系统将需要随着时间的推移重复干预（例如，每周干预措施 分钟），但将实现完全植入系统无法实现的较高峰值功率。 系统将用于猪疼痛模型（周围神经毒性），该模型更好地模仿了人类对 与啮齿动物模型相比，药理学干预措施已经能够做到。临床前研究将包括 30天的试点研究，然后在Minipigs进行了6个月的研究。 总而言之，该项目将扩大对PBM诱导的轴突块的基本理解 迈向适合治疗慢性疼痛的翻译设备。