Chronic opiates during ontogeny: A microarray analysis

描述(由申请人提供)：直到最近，唯一的描述 新生儿阿片类戒断综合征适用于人类婴儿。然而， 人类环境的复杂性使得我们不可能将这些方面分开 因使用阿片类药物而戒断的药物，以及因滥用药物而戒断的药物 在其他药物中，糟糕的产前护理，营养不良，或无数种药物中的任何一种 这些孩子的母亲经历的其他并发症。三个小组， 包括我们的，已经详细描述了幼年大鼠的阿片类药物戒断综合症。 戒断综合症在发育过程中缓慢变化，达到、围绕 青春期，经常被描述的典型的戒断行为 对于成年动物来说。在神经方面既有相似之处，也有不同之处 婴幼儿和成人戒断的潜在底物。尽管神经细胞 调解退出行为的结构相似，有重要的 NMDA受体在调节这些行为中的作用的差异。NMDA 阻滞剂对7日龄戒断症状没有影响或恶化，但可改善戒断症状 它在21日龄时出现。相反，一氧化氮合酶(NOS)抑制剂可阻断 在整个发展过程中退出。因此，在年轻时，NMDA受体和一氧化氮合酶 差别化监管突发性撤资。因为节欲 婴儿的综合症现在被非常详细地描述，我们准备问一个 一些以前无法解决的问题。特别是 关于阿片类药物依赖引起的基因变化和 在成年动物中退出，而在婴儿中则一无所知。这个 这里提出的实验定义了阿片剂诱导的基因表达的变化 在不同的发展阶段退出。我们在7点测试吗啡戒断 以及21日龄使用和不使用NMDA阻滞剂和NOS抑制剂来评估 在下列条件下基因表达模式的具体变化 撤回表示或不表示撤回。我们使用基因芯片技术来评估 基因表达模式的特定变化与高级生物信息学 方法来分析并提供对这些数据的访问。在每种情况下，我们都分析了 参与撤军的中枢神经系统特定区域，包括 中脑、蓝斑、杏仁核、中脑导水管周围灰质 伏隔和脊髓。通过评估表达的同时变化 大量的基因水平，我们就可以识别生物的本质 特定脑区对阿片类药物戒断的反应。反过来，这些数据 使我们能够更全面地了解 婴儿和成人之间的药物反应差异，并提供详细的 与基因表达模式相关的发育变化图解 阿片类药物戒断的严重程度。这些结果然后可以指导发展 阿片类药物戒断综合征的新治疗方法 有风险的婴儿。

DESCRIPTION (provided by applicant): Until recently the only description of an opiate abstinence syndrome in neonates was for human infants. Yet the complexities of the human setting make it impossible to tease apart the aspects of withdrawal that are due to opiate use, and those that are due to the abuse of other drugs, poor prenatal care, under-nutrition, or any of the myriad of other complications experienced by the mothers of these children. Three groups, including ours, have detailed an opiate withdrawal syndrome in the infant rat. The withdrawal syndrome slowly changes over development to reach, around puberty, the classic constellation of withdrawal behaviors so often described for the adult animal. There are both similarities and differences in the neural substrates underlying withdrawal in infants and adult. Although the neural structures mediating withdrawal behaviors are similar, there are important differences in the role of NMDA receptors mediating these behaviors. NMDA blockers have no effect, or worsen, withdrawal at 7 days of age but ameliorate it at 21 days of age. In contrast, nitric oxide synthase (NOS) inhibitors block withdrawal throughout development. Thus at young ages, NMDA receptors and NOS differentially regulate precipitated withdrawal. Because the abstinence syndrome in the infant is now described in great detail, we are poised to ask a number of questions that could not have been addressed before. In particular little is known of the genetic changes induced by opiate dependence and withdrawal in the adult animal, and nothing is known in the infant. The experiments proposed here define changes in gene expression induced by opiate withdrawal at different stages of development. We test morphine withdrawal at 7 and 21 days of age with and without NMDA blockers and NOS inhibitors to assess specific changes in patterns of gene expression under conditions where withdrawal is or is not expressed. We use gene microarray technology to assess specific changes in patterns of gene expression and advanced bioinformatic methods to analyze and provide access to these data. In each case we assay specific regions of the CNS involved in withdrawal, including the periaqueductal gray of the midbrain, the locus ceruleus, amygdala, nucleus accumbens and spinal cord. By assessing simultaneous changes in expression levels of large numbers of genes, we can identify the nature of the biological responses of specific brain regions to opiate withdrawal. In turn, these data allow a more complete understanding of the mechanisms underlying the differences in drug response between infants and adults, and provide a detailed picture of the developmental changes in patterns of gene expression linked to severity of opiate withdrawal. These results can then direct the development of novel treatments for the opiate withdrawal syndrome in this population of at risk infants.