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

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.