Novel Protein Biomarkers of Chronic Pain: Cross-Sectional and Longitudinal Analyses Using the DVCIPM Pain Registry Biobank

Project Summary/ Abstract Chronic pain is highly prevalent in the United States, affecting approximately 21% (~50 million) of adults, and is associated with substantial impairments in sleep, physical function, cognition, mental health, and quality of life. Pain is commonly treated with pharmacologic therapies, including opioids, that have undesirable and sometimes dangerous side effects, and yet many individuals continue to experience inadequate pain relief. These existing pharmacologic options are often limited by adverse events, reduced long-term effectiveness, and risks related to dependence and misuse. These limitations highlight the urgent need to identify novel, non- opioid, biologically informed targets to improve pain management and reduce reliance on opioids. Oxidative stress and mitochondrial dysfunction are increasingly recognized as mechanistic contributors to chronic pain through pathways involving neuroinflammation, altered cellular energetics, and sensitization of peripheral and central nociceptive systems. Solute carrier (SLC) transport proteins, including SFXN2/3/4/5, SLC22A14/15/31, and SLC25A39/42, regulate iron metabolism, NAD⁺ transport, amino acid trafficking, and electron flux; processes tightly coupled to oxidative stress and nociceptor excitability. In addition, select proteins involved in ion transport, calcium signaling, immune and membrane trafficking, and proteostasis (TM9SF2, MFSD2B, CALHM5, ENKUR, TMC5, TMEM638, TMPRSS9, PSMA8) represent complementary, understudied biological regulators of pain-relevant pathways. These targets remain largely unstudied in human pain populations, representing a critical gap and an opportunity for early-stage discovery of novel pain targets. Consequently, we propose a biobank-based observational study leveraging the Defense and Veterans Consortium for Integrative Pain Management (DVCIPM) Pain Registry Biobank to evaluate whether select understudied biologically relevant proteins are associated with pain-related outcomes. This project aligns with the mission of the NIH Helping to End Addiction Long-term (HEAL) Initiative and the National Center for Complementary and Integrative Health (NCCIH) by advancing rigorous, mechanistic research to identify new, non-opioid pain targets within the understudied druggable proteome. The proposed study will (1) quantify cross-sectional associations between candidate proteins and validated pain and physical function outcomes; (2) evaluate longitudinal associations between changes in biomarker levels and corresponding changes in pain-related symptoms over 1–3 months; and (3) rank targeted proteins according to their relative association with pain at baseline and with changes in pain impact, sleep, and physical functioning over 1–3 months. If successful, this study will provide foundational human evidence linking understudied transport proteins to clinically relevant pain outcomes using paired plasma biospecimens and validated patient-reported measures. These findings will accelerate early-stage identification of novel, druggable pain targets, support future biomarker-guided and mechanistic studies, and directly advance the goals of the HEAL Initiative.