Xie Yihan, Guessoum Omar, Schug Johnathan, Jo Adrienne, Cullen D Kacy, Kaestner Klaus H, Blendy Julie A
Department of System Pharmacology and Translational Therapeutics, School of Engineering and Applied Science, University of Pennsylvania.
Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania.
Res Sq. 2025 Aug 18:rs.3.rs-7199524. doi: 10.21203/rs.3.rs-7199524/v1.
Opioid Use Disorder (OUD) is a multifaceted neuropsychiatric disease that can arise from genetic, environmental, and neurobiological factors. The A118G single nucleotide polymorphism (rs1799971) encodes an N40D variant in the μ-opioid receptor (MOR) and is linked to increased risk of opioid and other drug dependencies, though its exact mechanism remains unknown. With the ongoing opioid crisis driving record overdose deaths, understanding how this variant influences addiction risk could open new therapeutic avenues. We applied a systematic, cross-modality platform to assess cell dynamics using spatial transcriptomics and uncover not only distinct spatially resolved transcriptome changes in opioid exposed mice, but also changes dependent on the variant. Collectively, our findings suggest that genetic risk for opioid dependence at the locus may be reflected more strongly in glial cell adaptations rather than neuronal dysfunction, emphasizing the importance of oligodendrocyte-mediated neuroimmune interactions in opioid dependence.
阿片类物质使用障碍（OUD）是一种多方面的神经精神疾病，可能由遗传、环境和神经生物学因素引起。A118G单核苷酸多态性（rs1799971）在μ-阿片受体（MOR）中编码N40D变体，与阿片类物质及其他药物依赖风险增加有关，但其确切机制尚不清楚。随着持续的阿片类物质危机导致过量用药死亡人数创下纪录，了解这种变体如何影响成瘾风险可能会开辟新的治疗途径。我们应用了一个系统的跨模态平台，使用空间转录组学来评估细胞动态，不仅揭示了阿片类物质暴露小鼠中不同的空间分辨转录组变化，还揭示了依赖于该变体的变化。总的来说，我们的研究结果表明，该位点阿片类物质依赖的遗传风险可能在胶质细胞适应中比在神经元功能障碍中更强烈地反映出来，强调了少突胶质细胞介导的神经免疫相互作用在阿片类物质依赖中的重要性。
