Chronic pain is a significant problem after nerve injury from trauma or surgery. Current therapies and attempts at prevention have proven largely ineffective. Through analysis of data obtained in the Molecular Signatures of Chronic Pain Subtypes study termed Veterans Integrated Pain Evaluation Research (VIPER) (W81XWH-11-2-0003) we have discovered two novel pain pathways with potential therapeutic relevance (Wnt and TGR5). In addition, we recognize that improving the safety and efficacy of existing therapies must continue to be a priority and plan to use the large pharmacogenomic database at Vanderbilt University to identify patients at risk for adverse opioid related events. The current proposal intends to study the contribution of non-neuronal immune cells (macrophages) to chronic pain while also evaluating novel analgesics in relevant animal models. The current proposal also attempts to determine the optimal patient population for opioid therapy while identifying those patients at greatest risk from opioids.