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）：对阿片类药物成瘾的趋势日益增加，这是怀孕期间至关重要的问题。怀孕阿片类药物替代者的替代疗法的新选择包括丁丙诺啡，一种阿片受体部分激动剂和kappa-阿片类药物受体拮抗剂。但是，缺乏有关该药物对儿童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，围产期暴露于丁丙诺啡会影响发育中的大鼠脑中的髓鞘形成。丁丙诺啡的治疗水平引起髓磷脂碱性蛋白（MBP），寡胶质细胞和髓磷脂成分的四个主要剪接同工型的加速脑表达，它们被认为是成熟的少突胶质细胞（OLGS）的标记。相比之下，该药物的上治疗水平会导致MBP表达的发育延迟，并减少骨髓的轴突数量。令人惊讶的是，对call体的分析表明，无论剂量如何，暴露于丁丙诺啡的幼虫都会显着增加骨髓轴突的能力。此外，这些轴突的特征是髓鞘较薄。基于这些观察结果，该提案基于以下中心假设：围产期暴露于丁丙诺啡和干扰内源性阿片类药物系统原因（1）异常OLG发育和（2）在神经神经元相互作用水平上对骨髓蛋白与髓质蛋白与radial轴突生长的协调至关重要的显着变化。考虑到这些可能性，具体的目标1将使用围产期丁丙诺啡暴露和少突胶质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将研究丁丙诺啡对髓鞘轴突的轴突细胞骨架的作用，研究轴突特征的潜在变化，被认为受髓神经胶质细胞所调节的轴突特征，包括神经丝的积累，间隔和磷酸化，以及CDK5和ERK1/2的局部分布，涉及CDK1/2的局部分布。丁丙诺啡动物模型的进一步表征将提供一种新颖而重要的工具，以研究阿片类药物系统作为寡头神经元相互作用的调节剂的作用，这是阿片类药物的功能，从未研究过。此外，在该项目的这个仍在探索的阶段中鉴定丁丙诺啡作用将为未来的研究提供稳固的基础，以研究该药物在复杂的成瘾模型中的影响，这将在怀孕的成瘾者中发生，事先暴露于其他阿片类药物和滥用药物中。对这些影响的清晰了解对于孕妇的阿片类药物成瘾者的管理策略的设计至关重要，从而最大程度地减少了成熟大脑中的有害影响。公共卫生相关性：阿片类模拟丁丙诺啡目前正在接受孕妇阿片类药物瘾君子的管理试验。但是，我们的研究表明，该药物可能会影响髓磷脂的形成，髓磷脂是促进神经冲动传导的膜。拟议的研究将进一步表征丁丙诺啡围产期暴露的动物模型，为将来的研究提供了对药物在复杂模型中的影响的稳固基础，这将考虑在怀孕的成瘾者中，事先暴露于其他阿片类药物和滥用药物中。对这些影响的清晰了解对于孕妇的阿片类药物成瘾者的设计和管理策略至关重要，最大程度地减少了成熟中枢神经系统中的有害影响。