ABSTRACT Chronic pain and opioid misuse are two intertwined health crises in the US. We know more about how chronic pain develops than how it naturally resolves. Our hypothesis is that the disruption of endogenous pro-resolution mechanisms causes chronic pain, and targeting these mechanisms can lead to more effective and safe pain treatment. Our grant proposal entitled "Cellular Mechanisms and Therapeutic Potential of NR4A1 in Pain Resolution" aims to investigate the nuclear receptor subfamily 4, group A, member 1 (NR4A1) as an endogenous mediator for pain resolution. Evidence suggests that NR4A1 limits inflammation and restores homeostasis in various diseases. However, its role in pain is unknown. In our preliminary studies, we discovered that NR4A1 is expressed in macrophages and increases during the resolution phase of in a mouse model of postoperative pain. Furthermore, we demonstrated that lack of NR4A1 expression results in chronic postoperative pain, whereas its activation accelerates recovery from postoperative pain. Thus, we hypothesize that NR4A1 in monocytes/macrophages is essential for pain resolution and limits chronic pain, and as a peripheral and endogenous mechanism may offer a more effective and safer therapeutic target for the treatment of pain. We have three specific aims to test this hypothesis. Specific Aim 1 will test whether NR4A1 in macrophages controls the resolution of inflammation and postoperative pain induced by plantar incision in mice. Specific Aim2 will test the hypothesis that natural and FDA-approved NR4A1 agonists promote pain resolution without major liabilities. Specific Aim3 aims to test whether NR4A1 regulates the release of the secreted protein 1 (SPP1), a potential biological and functional biomarker for NR4A1 target engagement and pain resolution. Successfully achieving our specific aims is highly significant for the HEAL initiative because it will reveal new endogenous mechanisms of pain resolution and provide a translational validation of NR4A1 as a new, non-addictive, therapeutic target for two pain conditions at high risk of opioid abuse: postoperative pain and low back pain. Additionally, we will reveal SPP1 as a novel biological and functional biomarker for future testing and improve of multiple NR4A1 agonists aiming to prevent and treat chronic pain.

NARRATIVE The proposed study investigates the role of the nuclear receptor subfamily 4, group A, member 1 (NR4A1) in pain resolution, and aims to provide a translational validation of NR4A1 as a new, non-addictive, therapeutic target for postoperative pain and low back pain, two pain conditions at high risk of opioid abuse. Additionally, the study will reveal SPP1 as a novel biological and functional biomarker for future testing and improve of multiple NR4A1 agonists aiming to prevent and treat chronic pain.