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病理性疼痛治疗的评估

• 批准号: 10642688
• 负责人: Juanita J Anders
• 金额: $ 57.22万
• 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/10642688
• 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; Family suidae; Fiber; Foundations; Goals; Health; Heating; Hour; Human; Image; Implant; Intervention; Investigation; Light; Literature; Longitudinal Studies; Microtubules; Miniature Swine; Modeling; Nerve; Nerve Block; Neuritis; Neurons; Nociception; Operative Surgical Procedures; Opioid; Pain; Patients; Peripheral Nerves; 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; behavior test; chronic pain; chronic pain management; direct application; experience; first-in-human; implantable device; in vivo; insight; interest; neural; neurotransmission; nociceptive response; opioid overdose; pain model; pain reduction; pain relief; painful neuropathy; pharmacologic; photobiomodulation; pre-clinical; preclinical development; preclinical evaluation; preclinical study; prototype; response; sciatic nerve; standard of care; tool; transmission blocking; 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.

项目概要/摘要 最近的研究表明，当 ~808 至 830 nm 的光立即并置到目标神经元时 或轴突（毫米内）通过侵入性技术，C和Aδ纤维可以传递疼痛相关信息 暂时且可逆地“关闭”，而不影响较大的 A 纤维的功能。 随着光生物调节（PBM）效应的发展，这种光生物调节（PBM）效应作为基于植入设备的器件具有令人兴奋的可能性 治疗各种慢性疼痛综合征，包括神经性疼痛，该项目采取了重要步骤。 培养基本和机械的理解，并为翻译奠定基础。 在基本原理和机理理解方面——首先，PBM 剂量和波长对 轴突阻滞（在离体周围神经制剂中）和伤害性反应（在体内啮齿动物疼痛中） 模型）将被严格表征，这些数据将提供重要的机制洞察和转化。 其次，观察到的微管不稳定和由此产生的轴突静脉曲张的作用。 我们将作为独立观察的动作电位块机制的贡献者进行探索。 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（共焦显微镜和电子显微镜数据）将用于评估。 轴突静脉曲张对动作电位传播的影响最后是药理微管的影响。 将评估 PAB 剂量的（去）稳定剂。 在转化活动方面——该项目包括开发临床前级系统，允许 神经上的 PBM 长期应用，最终目标是证明长期 PBM 可以提供 在大型动物疼痛模型（猪）中具有持久而深刻的镇痛效果 完全植入的系统。 基于现有商业神经刺激器的 PBM 将使 PBM 能够在较长时间内提供。 经皮系统需要随着时间的推移进行重复干预（例如，每周进行以下顺序的干预）： 分钟），但将能够使用完全植入式系统无法实现的更高峰值功率。 系统将用于猪疼痛模型（周围神经炎），该模型更好地模仿人类对疼痛的反应 临床前研究将包括比啮齿动物模型能够进行的药物干预。 在小型猪中进行为期 30 天的试点研究，然后进行为期 6 个月的研究。 总之，该项目将扩展对 PBM 诱导的眼睛轴突阻滞的基本理解 开发适合治疗慢性疼痛的转化设备。