Summary The COVID-19 pandemic and its effect on the opioid crisis have created a pressing need for telemedicine and consideration for use of non-pharmacological, low cost interventions as adjuvants in pain management arsenal. We propose a project investigating neural mechanisms underlying pain reduction induced by immersive Virtual Reality (VR). VR consists of immersion in artificial environments through the use of real-time rendering technologies and latest generation devices. We have recently demonstrated that VR increases pain tolerance limits and vagal activity with a parallel improvement in individual pain unpleasantness, mood, and situational anxiety. To enhance the translatability of this project, we will directly dive into the neural mechanisms of VR in chronic pain participants suffering from Temporomandibular Disorder(s) (TMD), a population with which the PI and her collaborators have had fruitful results. The overarching goal is to investigate the pain modulation mechanisms underlying VR-induced hypoalgesia by determining 1) the involvement of endogenous mu opioids, 2) the relationship between responsiveness to acute VR and long-term pain-related outcomes, and 3) the changes in cortical excitability related to 3-week VR. We will use three main approaches: 1) a pharmacological antagonist approach, 2) An ecological momentary assessment (EMA) for tracking dynamics of pain outcomes over 6 months; and 3) a high-resolution electroencephalography to measure synchronization of peak alpha frequency (PAF). We will disentangle the mechanisms of VR-induced hypoalgesia from placebo effects among participants with distinct disabilities and grades of TMD. We expect that 1) VR, similar to placebo effects, will reduce pain through the engagement of endogenous opioid systems, 2) VR-induced pain modulation capability will result in better long-term pain outcomes, and 3) 3-week VR will favor a synchronization of PAF oscillations paralleled by individual VR therapeutic benefits. This project will combine pharmacologic, the EMA, and electroencephalographic techniques employed within TMD patients to maximize the translational value of the resulting knowledge. The team has a history of successful collaboration and the expertise to generate innovative, relevant, and timely findings. The successful completion of this research will generate mechanistic-based evidence for the potential application of VR-based interventions which might empower TMD patients with new, accessible, and affordable therapeutic solutions.