The opioid system and brain development: effects of methadone on the oligodendrocyte lineage and the early stages of myelination.
The opioid system and brain development: effects of methadone on the oligodendrocyte lineage and the early stages of myelination.
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DOI：
10.1159/000365074
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发表时间：
2014
影响因子：
2.9
通讯作者：
Sato-Bigbee C
中科院分区：
文献类型：
--
作者：
Vestal-Laborde AA;Eschenroeder AC;Bigbee JW;Robinson SE;Sato-Bigbee C
少突胶质细胞在整个发育过程中表达阿片受体，但阿片系统在髓鞘形成中的作用仍然知之甚少。这是一个重要的问题，因为阿片类药物的使用和滥用在两个特定人群中继续增加：妊娠成瘾者，其中药物作用可能针对胎儿和新生儿的早期髓鞘形成;青少年和年轻人，其中“高阶”区域的髓鞘形成较晚。阿片类成瘾者的维持治疗包括长效阿片类药物美沙酮和丁丙诺啡。与我们以前对丁丙诺啡影响的研究结果相似，我们现在发现，围产期暴露于治疗剂量的美沙酮也会改变发育中大鼠大脑的早期髓鞘形成。暴露于这种药物的幼崽表现出髓鞘碱性蛋白（MBP），髓鞘蛋白脂质蛋白（PLP）和髓鞘少突胶质细胞糖蛋白（MOG）的四种主要剪接变体的脑水平升高。与这些蛋白在成熟髓鞘中的富集和功能一致，对这些年轻动物的胼胝体的分析也表明具有已经高度致密的髓鞘的轴突数量增加。此外，对培养细胞的研究表明，美沙酮在少突胶质细胞谱系的特定阶段发挥直接作用，刺激祖细胞的增殖，同时另一方面加速分化程度更高但仍不成熟的前少突胶质细胞的成熟。虽然这些观察结果的长期影响仍然未知，但加速或增加的少突胶质细胞成熟和髓鞘形成都可能破坏导致发育中大脑正常连接的同步事件的复杂序列。结合我们之前对丁丙诺啡作用的观察，本研究结果进一步强调了内源性阿片系统在控制少突胶质细胞发育和髓鞘形成时间方面的关键功能。阿片类药物的使用或维持治疗对这些调节系统的干扰可能会在髓鞘形成的关键阶段破坏大脑成熟的正常过程。
Oligodendrocytes express opioid receptors throughout development but the role of the opioid system in myelination remains poorly understood. This is a significant problem as opioid use and abuse continue to increase in two particular populations: pregnant addicts where drug effects could target early myelination in the fetus and newborns; and adolescents and young adults where late myelination of “higher-order” regions takes place. Maintenance treatments for opioid addicts include the long-lasting opioids methadone and buprenorphine. Similar to our previous findings on buprenorphine effects, we now find that early myelination in the developing rat brain is also altered by perinatal exposure to therapeutic doses of methadone. Pups exposed to this drug exhibit elevated brain levels of the four major splicing variants of myelin basic proteins (MBPs), myelin proteolipid protein (PLP), and myelin-oligodendrocyte glycoprotein (MOG). Consistent with the enrichment and function of these proteins in mature myelin, analysis of the corpus callosum in these young animals also indicated elevated number of axons with already highly compacted myelin sheaths. Moreover, studies in cultured cells showed that methadone exerts direct effects at specific stages of the oligodendrocyte lineage, stimulating the proliferation of the progenitor cells while on the other hand accelerating the maturation of the more differentiated but still immature pre-oligodendrocytes. While the long-term effects of these observations remain unknown, accelerated or increased oligodendrocyte maturation and myelination could both disrupt the complex sequence of synchronized events leading to normal connectivity in the developing brain. Together with our previous observations on buprenorphine effects, the present findings further underscore a crucial function of the endogenous opioid system in the control of oligodendrocyte development and the timing of myelination. Interference with these regulatory systems by opioid use or maintenance treatments could disrupt the normal process of brain maturation at critical stages of myelin formation.
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影响因子：
1.3
作者：
Chen, CY;Lee, KW;Zimmerman, RA
通讯作者：
Zimmerman, RA
影响因子：
2.3
作者：
Adamsbaum, C;Pinton, E;Kalifa, G
通讯作者：
Kalifa, G
影响因子：
2.8
作者：
Duprez, T;Ghariani, S;Evrard, P
通讯作者：
Evrard, P
影响因子：
6.2
作者：
Eschenroeder, Andrew C.;Vestal-Laborde, Allison A.;Sato-Bigbee, Carmen
通讯作者：
Sato-Bigbee, Carmen
DOI：
10.1016/j.ijdevneu.2013.02.009
发表时间：
2013-06
期刊：
International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience
影响因子：
--
作者：
Bajic D;Commons KG;Soriano SG
通讯作者：
Soriano SG