Department of Pediatrics, University of California, San Diego, La Jolla, CA, 92093, USA.
Department of Neurosciences, University of California, San Diego, La Jolla, CA, 92093, USA; Rady Children's Hospital, San Diego, CA, 92123, USA.
Neuropharmacology. 2023 Nov 15;239:109683. doi: 10.1016/j.neuropharm.2023.109683. Epub 2023 Aug 3.
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.
丁丙诺啡（BUP）和美沙酮（MTD）用于阿片类药物使用障碍的药物辅助治疗（MAT）。尽管这两种药物在妊娠期间与非法阿片类药物相比显示出改善的母婴和新生儿结局，但 BUP 对新生儿的结局比 MTD 更有利。BUP 和 MTD 之间差异的潜在细胞和分子机制在很大程度上尚不清楚。在这里，我们研究了暴露于 BUP 或 MTD 的人皮质类器官（hCO）的生长和神经元活性。我们发现，MTD 处理的 hCO 生长明显受到限制，而 BUP 处理的 hCO 则不受限制，并且 BUP 减弱了 MTD 在 hCO 中的生长限制作用。此外，κ-受体激动剂限制而拮抗剂减轻了 MTD 在 hCO 中的生长限制作用。由于 BUP 不仅是μ-激动剂，还是κ-拮抗剂，因此 BUP 预防这种生长限制可能是由于其κ-受体拮抗作用。此外，使用多电极阵列（MEA）技术，我们发现 BUP 和 MTD 均抑制了 hCO 中的神经元活性，但 BUP 仅在较高浓度下显示出抑制作用。此外，κ-受体拮抗剂 nBNI 不能预防 MTD 诱导的 hCO 中神经元活性的抑制，但 MTD 的 NMDA 拮抗作用（BUP 缺乏）在抑制神经元活性中起作用。我们得出结论，尽管 MTD 和 BUP 都是μ-阿片类激动剂，a）BUP 的额外 κ-受体拮抗作用减轻了神经发育过程中 MTD 诱导的生长限制，b）BUP 缺乏 NMDA 拮抗作用（与 MTD 相反）对神经网络通讯的抑制作用要小得多。
