Imaging Brain Kappa Opioid Receptors in Early Abstinence Opioid Use Disorder

Abstract Imaging Brain Kappa Opioid Receptors in Early Abstinence Opioid Use Disorder The opioid epidemic is one of the worse U.S. public health crises of the past three decades [1]. In response to this epidemic, the National Institute of Health launched a multi-pronged initiative a goal to develop new medications for the treatment of Opioid Use Disorder (OUD) [2]. The kappa Opioid Receptor (NOR) system is a significant driver of continued opioid use, due to its role in negative reinforcement (i.e., the alleviation of negative affect) often referred to as as the “Dark Side of Addiction.” Yet, understanding the role of NOR in OUD, particularly in human subjects, remains in its infancy. To address this gap, we conducted the first preliminary human Positron Emission Tomography (PET) imaging of NOR in people with OUD and saw lower [11C]EKAP binding among abstinent individuals with OUD vs. healthy controls. Our first aim is to use [11C]EKAP PET imaging to compare the magnitude and regional pattern of NOR availability (volume of distribution, VT) of inpatient early abstinent (within 5-10 days of admission) individuals with moderate to severe OUD (N = 40) as compared to matched outpatient healthy controls (HC; N = 30). Our second aim is to establish the clinical and transdiagnostic relevance of NOR by testing whether individual differences in NOR availability: (i) are linked to individual differences in post-inpatient patterns of opioid-use among individuals with OUD; and (ii) are linked to individual differences in experiences of negative affect and anhedonia across all participants (OUD and HC individuals). As tertiary aim: we will establish the clinical and transdiagnostic neural functional correlates of individual differences in NOR by testing whether: (i) individual differences in NOR availability, among OUD subjects, are linked to individual differences in patterns of functional connectivity within a previously identified `opioid abstinence network'[3]; and (ii) if we can identify a transdiagnostic functional neural signature of NOR availability across OUD and HC subjects. This research will help fill current gaps by providing not only the first human PET data specific for NOR in OUD but also the largest PET imaging study to date on opioid receptors in this population. It will also be the first to use multi-modal techniques to explore fMRI correlates of functional connectivity within the OUD group and across transdiagnostic domains (i.e., negative affect, anhedonia). As such, this proposal, paired with the current literature supporting NOR medications as one of the 10 most wanted pharmacological agents for rapid development in response to the Opioid Crisis [4], supports high impact and direct translational application of this work.