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Pharmacological treatments, particularly opioids, continue to be heavily relied upon for managing both acute and chronic pain conditions1. The effectiveness of pain management can be significantly affected by the frequency and severity of side effects associated with opioid use2. For this reason, a substantial amount of patients under opioid treatment do not achieve successful pain management3. Hence, pain physicians and the patient community are increasingly seeking non-pharmacological treatments that avoid the side effects associated with traditional pain medications. Photoneuromodulation has emerged as a promising solution and a safe therapy for managing pain.
Photoneuromodulation (PNM) is a non-invasive technique that uses light-emitting diodes (LED) to regulate biological processes4. Phototherapy was established thousands of years ago using sunlight, or heliotherapy, to treat skin conditions5. Subsequently, the concept of light influencing biological tissues has broadened, leading to the development of the photoneuromodulation term. PNM research is now expanding worldwide and has shown its effectiveness in a variety of clinical applications, including pain management6,7,8,9, improving sleep quality in patients with Alzheimer's disease10, and controlling depression11.
There is a growing emphasis on preclinical research and clinical trials aimed at investigating the mechanisms and therapeutic potential of photoneuromodulation for pain management. Among these approaches, green light-emitting diode therapy (GLED), using a 525 nm wavelength stimulation, has shown promising efficacy in reducing various types of pain, including migraines, fibromyalgia, and post-surgical pain12,13,14,15,16. Clinical trials have demonstrated that green light therapy consistently benefits patients suffering from migraine across multiple studies12,17,18, by reducing both headache pain and photophobia intensity during active migraine attacks19, as well as decreasing the frequency and duration of migraine episodes12. Preclinical studies also demonstrated that exposure to GLED can reverse thermal and mechanical hypersensitivity in a nerve injury model of neuropathic pain20. Further, preclinical studies have explored the mechanisms through which GLED influences pain perception and sensory thresholds13,21,22,23,24. These studies highlight the involvement of M-cones and the subsequent modulation of the ventral lateral geniculate nucleus (vLGN), which increases the activity of enkephalinergic neurons projecting to the dorsal raphe nucleus (DRN)22. Additional research has also emphasized the critical role of the rostral ventromedial medulla (RVM)21, a key regulator of descending pain modulation. Collectively, these findings suggest that GLED alters pain perception by modulating visual circuits that act on the descending pain pathways20,25. However, further research is required to facilitate its translation into clinical use.
In this article, we detail a comprehensive methodology for implementing GLED-based PNM, aiming to provide a reproducible framework for both experimental and clinical use. We describe the design and operation of GLED exposure, outline standardized application protocols, and discuss key considerations for ensuring efficacy and reproducibility. Additionally, we provide a detailed protocol for assessing the activity of both ascending and descending pain pathways, enabling a deeper investigation into their roles in modulating GLED-induced analgesia. By sharing this approach, we aim to advance research in non-pharmacological pain management and contribute to developing accessible, effective, and safer therapies.