Chronic opiates during ontogeny: A microarray analysis

描述（由申请人提供）：直到最近， 新生儿阿片类药物戒断综合征是人类婴儿。然而 人类环境的复杂性使得我们不可能将 戒断是由于阿片类药物的使用，而那些是由于滥用 其他药物，产前护理差，营养不良，或任何无数的 这些孩子的母亲经历的其他并发症。三组， 包括我们的，都详细描述了幼鼠的阿片类戒断综合征。 戒断综合征在发育过程中缓慢变化， 青春期是一系列典型的退缩行为， 对于成年动物来说。在神经系统中既有相似之处， 婴儿和成人戒断的基础物质。虽然神经 介导退出行为的结构是相似的，有重要的 NMDA受体介导这些行为的作用的差异。NMDA 阻滞剂对7日龄时的戒断症状没有影响或加重，但改善了 在21天的年龄。相反，一氧化氮合酶（NOS）抑制剂阻断了 在整个发展过程中退出。因此，在年轻时，NMDA受体和NOS 差异调节突然戒断。因为禁欲 婴儿综合征现在被详细描述，我们准备问一个问题。 许多以前无法解决的问题。特别是 对阿片类药物依赖引起的遗传变化知之甚少， 在成年动物中的戒断，在婴儿中什么都不知道。的 这里提出的实验定义了阿片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 和21日龄，使用和不使用NMDA阻滞剂和NOS抑制剂，以评估 基因表达模式的特定变化， 撤回是否表示。我们使用基因微阵列技术来评估 基因表达模式的特定变化和高级生物信息学 方法来分析和提供对这些数据的访问。在每种情况下，我们分析 涉及停药的CNS特定区域，包括 中脑导水管周围灰质，蓝斑，杏仁核，核团 脊椎和脊髓。通过评估表达的同时变化， 大量基因的水平，我们可以确定生物的性质， 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 基因表达模式的发育变化图， 阿片类药物戒断的严重性。这些结果可以指导开发 在这一人群中治疗阿片类药物戒断综合征的新方法 风险婴儿

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.