Buprenorphine effects on oligodendrocyte development and axonal growth

丁丙诺啡对少突胶质细胞发育和轴突生长的影响

基本信息

批准号：
7707791
负责人：
CARMEN SATO-BIGBEE
金额：
$ 20.51万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7707791
关键词：
Abstinence Address Affect Agonist Animal Model Animals Apoptosis Axon Brain Buprenorphine Caliber Cell Differentiation process Cells Characteristics Child Clinical Research Communication Complex Corpus Callosum Cytoskeleton Development Developmental Delay Disorders Dose Epidemiology Equilibrium Exhibits Exposure to Future Generations Growth Laboratories Lead Membrane Mind Modeling Molecular Myelin Myelin Associated Glycoprotein Myelin Basic Proteins Myelin Sheath Neonatal Neural Conduction Neuroglia Neurons Oligodendroglia Opioid Opioid Receptor Perinatal Perinatal Exposure Pharmaceutical Preparations Phosphorylation Phosphotransferases Pregnancy Process Protein Isoforms RNA Splicing Radial Rattus Role Solid Staging Surveys Symptoms System Testing Therapeutic addiction analog axon growth base design drug of abuse endogenous opioids in utero in vivo kappa opioid receptors mind control mu opioid receptors myelination neurofilament novel opioid abuse postnatal pregnant protein expression public health relevance pup research study tool trend

项目摘要

DESCRIPTION (provided by applicant): The increasing trend in the addiction to opioids is a problem of critical importance during pregnancy. New options for substitution therapies in pregnant opioid addicts include buprenorphine, a mu-opioid receptor partial agonist and kappa- opioid receptor antagonist. However, there is a lack of information on the potential effects of this drug on child brain development. In this regard, recent results from our laboratory showed that perinatal exposure to buprenorphine affects myelination in the developing rat brain. Therapeutic levels of buprenorphine caused an accelerated brain expression of the four major splicing isoforms of myelin basic protein (MBP), oligodendroglial and myelin components that are considered to be markers of mature oligodendrocytes (OLGs). In contrast, supra-therapeutic levels of the drug resulted in a developmental delay in MBP expression and a decrease in the number of axons that were myelinated. Surprisingly, analysis of the corpus callosum indicated that, regardless of the dose, pups exposed to buprenorphine exhibited a significant increase in the caliber of myelinated axons. Moreover, these axons were characterized by having a disproportionately thinner myelin sheath. Based on these observations, this proposal is based on the central hypothesis that perinatal exposure to buprenorphine and interference with the endogenous opioid system cause (1) abnormal OLG development and (2) significant alterations at the level of glial-neuronal interactions crucial to the coordination of myelin formation with radial axonal growth. With these possibilities in mind, Specific Aim 1 will use an animal model of perinatal buprenorphine exposure and oligodendroglial cultures to investigate buprenorphine effects on OLG development. Specific Aim 2 will study the effect of buprenorphine on the axonal cytoskeleton of myelinated axons, investigating potential alterations of axonal features thought to be regulated by the myelinating glial cells, including neurofilament accumulation, spacing and phosphorylation, and the local distribution of Cdk5 and ERK1/2, two major kinases involved in neurofilament phosphorylation . Further characterization of the buprenorphine animal model will provide a novel and important tool to investigate the role of the opioid system as a regulator of oligodendroglial-neuronal interactions, an opioid function never studied before. Moreover, identification of buprenorphine actions at this still exploratory stage of the project will provide solid bases for future studies on the effects of the drug in complex models of addiction that will consider, as it occurs in pregnant addicts, prior exposure to other opioids and drugs of abuse. Clear understanding of these effects is crucial to the design of management strategies for pregnant opioid addicts minimizing harmful effects in the maturing brain. PUBLIC HEALTH RELEVANCE: The opioid analogue buprenorphine is currently on trials for the management of pregnant opioid addicts. However, our studies indicated that this drug may affect the formation of myelin, a membrane that facilitates the conduction of nerve impulses. The proposed studies will further characterize the animal model of perinatal exposure to buprenorphine, providing solid bases for future studies on the effects of the drug in complex models of addiction that will consider, as it occurs in pregnant addicts, prior exposure to other opioids and drugs of abuse. Clear understanding of these effects is crucial to the design and management strategies for pregnant opioid addicts minimizing harmful effects in the maturing CNS.

描述（由申请人提供）：阿片类药物成瘾的增加趋势是怀孕期间至关重要的问题。妊娠阿片类药物成瘾者替代疗法的新选择包括丁丙诺啡、μ阿片受体部分激动剂和κ阿片受体拮抗剂。然而，缺乏关于这种药物对儿童大脑发育的潜在影响的信息。在这方面，我们实验室的最新结果表明，围产期接触丁丙诺啡会影响发育中的大鼠大脑的髓鞘形成。丁丙诺啡的治疗水平导致髓磷脂碱性蛋白（MBP）、少突胶质细胞和髓磷脂成分的四种主要剪接亚型的加速脑表达，这些成分被认为是成熟少突胶质细胞（OLG）的标志物。相反，超过治疗水平的药物会导致 MBP 表达发育延迟和有髓鞘轴突数量减少。令人惊讶的是，对胼胝体的分析表明，无论剂量如何，暴露于丁丙诺啡的幼崽的有髓轴突口径显着增加。此外，这些轴突的特点是具有不成比例的薄髓鞘。基于这些观察，该提议基于以下中心假设：围产期接触丁丙诺啡和干扰内源性阿片系统会导致（1）OLG 发育异常和（2）对协调至关重要的神经胶质-神经元相互作用水平的显着改变髓磷脂形成与径向轴突生长。考虑到这些可能性，具体目标 1 将使用围产期丁丙诺啡暴露和少突胶质细胞培养的动物模型来研究丁丙诺啡对 OLG 发育的影响。具体目标 2 将研究丁丙诺啡对有髓轴突的轴突细胞骨架的影响，研究被认为受髓鞘神经胶质细胞调节的轴突特征的潜在改变，包括神经丝积累、间距和磷酸化，以及 Cdk5 和 ERK1/ 的局部分布2、参与神经丝磷酸化的两种主要激酶。丁丙诺啡动物模型的进一步表征将为研究阿片类系统作为少突胶质细胞-神经元相互作用调节剂的作用提供一种新颖且重要的工具，这是一种以前从未研究过的阿片类功能。此外，在该项目仍处于探索阶段的丁丙诺啡作用的鉴定将为未来研究该药物在复杂成瘾模型中的作用提供坚实的基础，该模型将考虑怀孕成瘾者之前接触其他阿片类药物和药物的情况的虐待。清楚地了解这些影响对于设计怀孕阿片类药物成瘾者的管理策略至关重要，最大限度地减少对成熟大脑的有害影响。公共卫生相关性：阿片类药物类似物丁丙诺啡目前正在试验用于治疗怀孕阿片类药物成瘾者。然而，我们的研究表明，这种药物可能会影响髓磷脂的形成，髓磷脂是一种促进神经冲动传导的膜。拟议的研究将进一步描述围产期丁丙诺啡暴露的动物模型，为未来研究该药物在复杂成瘾模型中的影响提供坚实的基础，该模型将考虑怀孕成瘾者之前接触其他阿片类药物和药物的情况的虐待。清楚地了解这些影响对于怀孕阿片类药物成瘾者的设计和管理策略至关重要，最大限度地减少对成熟中枢神经系统的有害影响。