The Role of Pain-Facilitating Circuits in Chronic Pain after Traumatic Brain Injury - PROJECT SUMMARY Victims of mild traumatic brain injury (mTBI) commonly experience chronic pain, including headaches, spine and limb pain, and are at high risk of developing long-term disability and opioid misuse. Despite this recognized link between mTBI and chronic pain, the neurocircuitry underlying how mTBI increases pain is not known. Emerging preclinical data suggest that the function of a major brainstem pain-modulating circuit, rostral ventromedial medullar (RVM), is disrupted after mTBI - although the precise mechanism is still elusive. The RVM can either enhance or suppress pain. Its pain-facilitating function is mediated by a distinct cell class, ON-cells, which can increase noxious signal transmission through their projections to the spinal dorsal horns. The central hypothesis of this project is that mTBI contributes to chronic pain by sensitizing RVM ON-cell activity, which increases the body’s sensitivity to both noxious and normally innocuous stimuli. In a mouse model of mTBI, my preliminary results suggest that 1) mTBI leads to increased sensitivity in periorbital allodynia (a model for headache) and hindpaw allodynia (a model for distal pain), and 2) an intact ON-cell circuit is required for the development of persistent post-mTBI pain. In two Specific Aims, this study will test the hypothesis by characterizing the functional and electrophysiological changes in descending ON-cells (e.g., spinal/trigeminal dorsal horn-projecting) following mTBI. First, the functional role of descending ON-cells in mTBI-induced hypersensitivity to postsurgical pain (Aim 1a) and headache (Aim 1b) will be explored through the use of chemogenetics. Second, the progressive changes in ON-cell activity in animals with mTBI, and subsequent postsurgical pain (Aim 2a) and headache (Aim 2b) will be studied using in vivo calcium fiber photometry. Finally, the synaptic characteristics of these descending ON-cells in post-mTBI animals with persistent postsurgical pain and headache will be investigated using ex vivo patch clamp recording in RVM brain slices (Aim 2c). This project will provide foundational information to establish the relationship between brainstem pain modulation and brain injury. By defining the longitudinal changes in a highly important pain-facilitating circuit underlying TBI-related pain, the proposed studies address a critical knowledge gap in how TBI leads to chronic pain. Successful completion of this work could also more broadly facilitate our understanding of other centralized pain conditions. Dr. Chen is a physician-scientist with a diverse training background in anesthesiology, pain medicine, and basic neuroscience research. In addition to its scientific significance, this project will enhance his expertise in animal genetics, neural circuit manipulation, in vivo photometry and ex vivo neurophysiological recording, as well as lay the foundation for his future work in pain research and inform clinical practice. The detailed career development presented in this application will provide the required resources and mentorship for Dr. Chen to become an independent R01-funded investigator studying the pathophysiology of brainstem pain modulation neural networks affected by brain injuries.
