Tarbiat Modares University Pathobiology Research 2538-3000 28 2 2025 03 01 Computational Analysis of GPCR Networks in Opioid Use Disorder: From Transcriptomics to Drug Discovery 35 49 19539 EN Narjes Khatoun Shabani Sadr Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran Mahsa Mirzaei Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran Mehrdad Behmanesh Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, IranInstitute for Brain and Cognition, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran Journal Article <span>Introduction:</span><span> Opioid Use Disorder (OUD) is a chronic neuropsychiatric condition driven by persistent neuroadaptive changes in reward, motivation, and stress-related circuits. While opioid receptors are central to OUD, the broader role of G protein-coupled receptors (GPCRs) in opioid-induced neuroplasticity remains underexplored. This study systematically characterizes GPCR dysregulation in OUD to identify potential pharmacological targets. Methods: We performed transcriptomic analysis of RNA sequencing (RNA-seq) datasets from addiction-related brain regions, including th<span>e dorsolateral prefrontal cortex (DLPFC)</span> and nucleus accumbens (GSE174409), Brodmann area 9 (GSE182321), and central amygdala (GSE194368). A curated set of ~900 GPCR genes was analy<span>zed for differentially expressed genes (DEG), pri</span>ncipal component analysis (PCA), and hierarchical clustering. Drug-targetable GPCRs were identified via DrugBank and ChEMBL, and their behavioral and stress-related roles were determined. Protein-protein interaction (PPI) networks were constructed using STRING. Results: We identified 58 GPCRs consistently dysregulated across brain regions, reflecting common molecular adaptations in OUD. PCA revealed a clear separation between OUD and control groups, indicating distinct receptor remodelin<span>g. Hierarchical clustering identified functional subgroups, including drug-targetable GPCRs and orphan GPCRs. </span>Notably, 17 GPCRs—including DRD1, DRD3, DRD4, HTR1A, HTR2A, OXTR, and CNR1—are involved in behavioral regulation and addiction vulnerability. Network analysis highlighted key receptor hubs, suggesting novel therapeutic targets. Conclusion: <span>The present s</span>tudy provides a receptor-centric framework for drug repurposing and precision medicine in OUD. Integrating transcriptomic and pharmacological data, we highlight GPCRs with translational potential. Further validation through functional assays and single-cell studies is warranted.</span> https://mjms.modares.ac.ir/article_19539_a3dd176fb68ba78b8297421f5a093f24.pdf