Project Summary/Abstract Opioid use disorder (OUD) has reached an epidemic scale in the United States. OUD is a complex neuro- behavioral disorder influenced by neurobiological, genetic, and environmental factors. Recently, there has been increased interest in the role of the neuroimmune system in OUD. Neuroimmune signaling has been shown to influence both appetitive (e.g., opioid craving, opioid-seeking behavior) and dysphoric (e.g., pain sensitivity, opioid withdrawal symptoms) addiction processes. Preclinical findings indicate that acute opioid administration evokes pro-inflammatory responses in both the periphery and brain. However, the effects of chronic opioid abuse on the in vivo neuroimmune system are not well-understood. The goal of this study is to apply multi-modal imaging to investigate whether the neuroimmune system is disrupted in OUD patients who are early in outpatient methadone maintenance therapy, stable, and not abusing illicit opioids. Specifically, we will use Positron Emission Tomography (PET) α-[11C]methyl-L-tryptophan ([11C]AMT) and proton magnetic resonance spectroscopy (1H MRS) myo-Inositol imaging among OUD patients contrasted with well-matched healthy volunteers. OUD patients will be monitored for up to six months via thrice weekly urine drug screens to determine time to opioid lapse. PET [11C]AMT imaging facilitates quantitative measure of metabolic activity in the kynurenine pathway: a pathway that is sensitive to pro-inflammatory neuroimmune stimuli. 1H MRS myo- Inositol is a putative glial marker thought to be upregulated by astrocyte activation. Together, these markers will clarify whether chronic opioid abuse is associated with neuroimmune system disruption and whether neuroimmune marker levels early-in-treatment prospectively predict treatment response in standard-of-care outpatient methadone maintenance therapy. Results from this study may inform novel interventions, such as glial modulator medications, to supplement medication-assisted therapies for patients with OUD. This Career Development Award will facilitate Dr. Woodcock’s progression toward his ultimate career goal of an independent research program investigating the role of the neuroimmune system in addiction.