Micah A. Shelton¹, Nicole Horan¹, Xiangning Xue², Lisa Maturin³, Darrell Eacret⁴, Julie Michaud⁵, Navsharan Singh⁶, Benjamin R. Williams⁷, Mackenzie C. Gamble^6,7, Joseph A. Seggio⁵, Madeline Kuppe-Fish⁷, BaDoi N. Phan⁸, George C. Tseng², Julie A. Blendy⁴, Leah C Solberg Woods⁹, Abraham A. Palmer³, Olivier George³, Marianne L. Seney^1*, Ryan W. Logan^7,10*

Opioid use disorder (OUD) has emerged as a severe, ongoing public health emergency. Current, frontline addiction treatment strategies fail to produce lasting abstinence in most users. This underscores the lasting effects of chronic opioid exposure and emphasizes the need to understand the molecular mechanisms of drug seeking and taking, but also how those alterations persist through acute and protracted withdrawal. Here, we used RNA sequencing in post-mortem human tissue from males (n=10) and females (n=10) with OUD and age and sex-matched comparison subjects. We compared molecular alterations in the nucleus accumbens (NAc) and dorsolateral prefrontal cortex (DLPFC) between humans with OUD and rodent models across distinct stages of opioid use and withdrawal (acute and prolonged) using differential gene expression and network-based approaches. We found that the molecular signature in the NAc of females with OUD mirrored effects seen in the NAc of female mice at all stages of exposure. Conversely, males with OUD showed strong overlap in expression profile with rats in acute withdrawal. Co-expression networks involved in post-transcriptional modification of RNA and epigenetic modification of chromatin state. This study provides fundamental insight into the converging molecular pathways altered by opioids across species. Further, this work helps to disentangle which alterations observed in humans with OUD are driven by acute drug exposure and which alterations are consequences of chronic exposure.

¹Department of Psychiatry, University of Pittsburgh School of Medicine
²Department of Biostatistics, University of Pittsburgh
³Department of Psychiatry, University of California, San Diego
⁴Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania
⁵Department of Biology, Bridgewater State University
⁶Department of Pharmacology, Physiology & Biophysics, Boston University School of Medicine
⁷Department of Psychiatry, University of Massachusetts Chan Medical School
⁸Medical Scientist Training Program, University of Pittsburgh School of Medicine
⁹Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine
¹⁰Department of Neurobiology, University of Massachusetts Chan Medical School
*Corresponding authors