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

项目概要/摘要 最近的研究表明，当~808至830 nm的光被施加在立即并列的目标神经元， 或轴突（mm内），传递疼痛相关信息的C和Aδ纤维可以 在不影响较大A型纤维的功能的情况下，可以暂时且可逆地“关闭”。如果进一步 开发，这种光生物调节（PBM）效应具有令人兴奋的可能性，作为一种基于植入式设备的 治疗各种慢性疼痛综合征，包括神经性疼痛。该项目采取重要步骤， 发展基本的和机械的理解，并为翻译提供基础。 在基本的和机械的理解方面-首先，PBM剂量和波长对 轴突阻滞（在离体外周神经制备中）和伤害性反应（在体内啮齿动物疼痛中 模型）将被严格描述。这些数据将提供重要的机械洞察力和翻译 值第二，观察到的微管不稳定和由此产生的轴突静脉曲张的作用将是 探索作为独立观察到的动作电位阻滞机制的贡献者。我们将 确定效应量（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位传播的影响。最后，药理微管的作用 将评估稳定剂对PAB剂量的影响。 在翻译活动方面-该项目包括开发临床前级系统， PBM长期应用于神经，最终目的是证明慢性PBM可以提供 在大型动物疼痛模型（猪）中具有持久和显著的镇痛作用。完全植入式系统 将使PBM能够在延长的时间段内输送。 经皮系统将需要随着时间的推移重复介入（例如，每周发言， 分钟），但将能够使用完全可植入系统无法实现的更高峰值功率。的 系统将用于猪疼痛模型（外周神经炎），该模型更好地模拟了人类对 药理学干预比啮齿动物模型已经能够做到。临床前研究将包括 30-在小型猪中进行为期6天的初步研究，然后进行为期6个月的研究。 总之，本项目将扩大对PBM诱导的轴突阻滞的基本理解， 涉及适于治疗慢性疼痛的平移装置。

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.