Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, USA.
Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA.
Transl Psychiatry. 2023 May 6;13(1):151. doi: 10.1038/s41398-023-02397-3.
Opioid use disorder (OUD) among pregnant women has become an epidemic in the United States. Pharmacological interventions for maternal OUD most commonly involve methadone, a synthetic opioid analgesic that attenuates withdrawal symptoms and behaviors linked with drug addiction. However, evidence of methadone's ability to readily accumulate in neural tissue, and cause long-term neurocognitive sequelae, has led to concerns regarding its effect on prenatal brain development. We utilized human cortical organoid (hCO) technology to probe how this drug impacts the earliest mechanisms of cortico-genesis. Bulk mRNA sequencing of 2-month-old hCOs chronically treated with a clinically relevant dose of 1 μM methadone for 50 days revealed a robust transcriptional response to methadone associated with functional components of the synapse, the underlying extracellular matrix (ECM), and cilia. Co-expression network and predictive protein-protein interaction analyses demonstrated that these changes occurred in concert, centered around a regulatory axis of growth factors, developmental signaling pathways, and matricellular proteins (MCPs). TGFβ1 was identified as an upstream regulator of this network and appeared as part of a highly interconnected cluster of MCPs, of which thrombospondin 1 (TSP1) was most prominently downregulated and exhibited dose-dependent reductions in protein levels. These results demonstrate that methadone exposure during early cortical development alters transcriptional programs associated with synaptogenesis, and that these changes arise by functionally modulating extra-synaptic molecular mechanisms in the ECM and cilia. Our findings provide novel insight into the molecular underpinnings of methadone's putative effect on cognitive and behavioral development and a basis for improving interventions for maternal opioid addiction.
孕妇阿片类药物使用障碍（OUD）已成为美国的一种流行病。治疗母体 OUD 的药物干预最常涉及美沙酮，一种合成阿片类镇痛药，可减轻与成瘾相关的戒断症状和行为。然而，美沙酮容易在神经组织中积累并导致长期神经认知后遗症的证据，引起了人们对其对产前大脑发育影响的担忧。我们利用人类皮质类器官（hCO）技术来研究这种药物如何影响皮质发生的最早机制。对用 1 μM 美沙酮以临床相关剂量慢性处理 50 天的 2 个月大 hCO 进行的批量 mRNA 测序显示，美沙酮与突触的功能成分、潜在的细胞外基质（ECM）和纤毛相关的转录反应强烈。共表达网络和预测蛋白-蛋白相互作用分析表明，这些变化协同发生，以生长因子、发育信号通路和基质细胞蛋白（MCPs）的调节轴为中心。TGFβ1 被鉴定为该网络的上游调节剂，并且作为 MCPs 的高度相互连接簇的一部分出现，其中血小板反应蛋白 1（TSP1）下调最为明显，并且蛋白水平呈剂量依赖性降低。这些结果表明，美沙酮在皮质早期发育过程中的暴露改变了与突触发生相关的转录程序，并且这些变化通过功能调节 ECM 和纤毛中的突触外分子机制而产生。我们的研究结果为美沙酮对认知和行为发育的潜在影响的分子基础提供了新的见解，并为改善母体阿片类药物成瘾的干预措施提供了依据。
