The Role of Pain-Facilitating Circuits in Chronic Pain after Traumatic Brain Injury

Veterans Admin Palo Alto Health Care Sys, Palo Alto CA

Investigators

Abstract

Traumatic brain injury (TBI), particularly mild TBI (mTBI, or “concussion”), is commonly associated with chronic pain, such as headache and generalized body pain. It also leads to prolonged pain and worse functional outcomes after subsequent injuries or surgeries, contributing to poor quality of life and opioid misuse. Despite this well-known link between mTBI and pain, one of the major obstacles to developing effective therapies specifically for mTBI-related pain is the critical knowledge gap concerning why patients with mTBI develop chronic pain. Emerging clinical and laboratory studies suggest that the endogenous pain- modulating system is disrupted after mTBI, impacting the interplay of pain-facilitating and pain-inhibiting circuits. The objective of the proposed project is to delineate the neurophysiological processes through which mTBI disrupts the endogenous pain-modulating circuits, thereby prolonging and intensifying pain. The best-studied pain-modulating circuit is the rostral ventromedial medulla (RVM), which exerts bidirectional modulatory effects by facilitating or inhibiting the passage of noxious input from the periphery through the dorsal horn. Activation of pain-facilitating neurons in the RVM, ON-cells, can increase pain sensitivity by establishing a transient positive feedback loop for nociception in response to noxious stimuli. However, sensitization of ON-cells and this pronociceptive loop has been implicated in several chronic pain conditions. The overarching hypothesis of this project is that mTBI contributes to a persistent pain state by sensitizing ON-cells after the initial head injury. This hypothesis will be tested through completion of two Specific Aims. First, the functional role of ON-cells in mTBI-induced hypersensitivity to postsurgical pain (Aim 1a) and headache (Aim 1b) will be explored through the use of chemogenetic methods and transgenic mice to selectively manipulate the ON-cell circuits. Second, the neurophysiology of ON-cells after mTBI (Aim 2a), and the progressive changes in their activity over time in response to subsequent surgical pain (Aim 2b) and environmental stresses (Aim 2c) will be studied using in vivo fiber photometry and calcium imaging. We expect that the sensitization of ON-cells is the principal driver for mTBI-related pain behaviors, and chemoinhibition of this pronociceptive circuit will attenuate both persistent postsurgical pain and headache after mTBI. There is now growing evidence that dysfunction of the brainstem pain modulation system is an important factor in many clinically significant pain states. This project addresses a critical knowledge gap by defining the circuits underlying the relationship between mTBI and chronic pain, and is unique for its functional delineations of the plasticity in a major pain-modulating system as pain behaviors evolve over time after mTBI. Successful completion of these studies will provide insights into functional changes in the pain-modulating system and pain persistence after mTBI, and could facilitate our understanding of other centralized pain conditions, such as Gulf War Illness. Identifying the central mechanistic targets underlying the sensitization of the endogenous pain modulation system is thus a crucial step toward better treatments for Veterans with TBI. In addition to the scientific significance, the proposed research will allow the PI, Dr. Chen, to become an expert in three technical domains critical to his long-term career goal at the VA: 1) the use of clinically relevant behavioral models for central pain syndromes; 2) the mastery of cutting-edge neuroscience tools, including chemogenetic techniques and fiber photometry; 3) the application of genetic tools to neurophysiology and circuit-focused pain research. The synergistic training and mentorship plans embedded in this CDA2 application will prepare Dr. Chen to obtain VA Merit Review and NIH funding by the time of project completion. With this CDA2 program, Dr. Chen is poised to become an independent VA investigator focusing on the functional contributions of endogenous pain modulation and other alterations of the CNS to clinically significant pain conditions and advancing Veteran healthcare as a pain management specialist.