哺乳母马（BUP）和美沙酮（MTD）被用于药物辅助治疗（MAT）阿片类物质使用障碍。尽管两种药物在孕期与非法阿片类物质使用相比，均表现出改善的孕产妇和新生儿结局，但BUP对新生儿的结果更为有利。关于BUP和MTD之间差异的细胞和分子机制尚不清楚。因此，我们在人类皮质器官样（hCO）细胞中检测了BUP和MTD的生长和神经活动。我们发现MTD处理后hCO的生长显著受限，而BUP处理后的hCO则未受限，并且BUP能够减轻MTD对hCO的生长限制效应。此外，κ-受体激动剂能够限制MTD对hCO的生长效应，而κ-受体拮抗剂则能减轻此效应。鉴于BUP不仅是μ-受体激动剂，也是κ-受体拮抗剂，BUP通过κ-受体拮抗作用可能预防了生长受限。此外，使用多电极阵列（MEA）技术，我们发现BUP和MTD均抑制了hCO的神经活动，但BUP仅在较高浓度下显示了抑制效应。此外，κ-受体拮抗剂nBNI无法阻止MTD引起的hCO神经活动抑制，而MTD（而非BUP）的NMDA拮抗作用在神经活动的抑制中发挥了作用。因此，虽然MTD和BUP都是μ-阿片受体激动剂，但a）BUP的额外κ-受体拮抗作用能够减轻MTD诱导的神经发育生长限制，b）BUP缺乏NMDA拮抗作用（相对于MTD）对神经网络通信的抑制效应更小。

Buprenorphine (BUP) and methadone (MTD) are used for medication-assisted treatment (MAT) in opioid use disorder. Although both medications show improved maternal and neonatal outcomes compared with illicit opioid use during pregnancy, BUP has exhibited more favorable outcomes to newborns than MTD. The underlying cellular and molecular mechanisms for the difference between BUP and MTD are largely unknown. Here, we examined the growth and neuronal activity in human cortical organoids (hCOs) exposed to BUP or MTD. We found that the growth of hCOs was significantly restricted in the MTD-treated but not in the BUP-treated hCOs and BUP attenuated the growth-restriction effect of MTD in hCOs. Furthermore, a κ-receptor agonist restricted while an antagonist alleviated the growth-restriction effect of MTD in hCOs. Since BUP is not only a μ-agonist but a κ-antagonist, the prevention of this growth-restriction by BUP is likely due to its κ-receptor-antagonism. In addition, using multielectrode array (MEA) technique, we discovered that both BUP and MTD inhibited neuronal activity in hCOs but BUP showed suppressive effects only at higher concentrations. Furthermore, κ-receptor antagonist nBNI did not prevent the MTD-induced suppression of neuronal activity in hCOs but the NMDA-antagonism of MTD (that BUP lacks) plays a role in the inhibition of neuronal activity. We conclude that, although both MTD and BUP are μ-opioid agonists, a) the additional κ-receptor antagonism of BUP mitigates the MTD-induced growth restriction during neurodevelopment and b) the lack of NMDA antagonism of BUP (in contrast to MTD) induces much less suppressive effect on neural network communications.Copyright © 2023. Published by Elsevier Ltd.