Microarray analysis of morphine's behavioral effects

吗啡行为影响的微阵列分析

• 批准号: 6776245
• 负责人: Gregory I Elmer
• 金额: $ 37.29万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-15 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6776245
• 关键词: analgesia; behavior prediction; behavioral /social science research tag; behavioral genetics; drug administration rate /duration; drug tolerance; fluorescent in situ hybridization; gene expression; gene expression profiling; gene mutation; genetically modified animals; genotype; intravenous administration; laboratory mouse; microarray technology; morphine; neuropharmacology; occipital lobe /cortex; periaqueductal gray matter; polymerase chain reaction; prefrontal lobe /cortex; psychopharmacology; self medication; statistics /biometry; temporal lobe /cortex

DESCRIPTION (provided by applicant): Opioids produce acute pharmacological effects valuable for the treatment of pain. Acute opioid administration also produces an euphoric state in recreational drug users. Repeated opioid administration, however, can lead to a progressive decline in analgesic efficacy and a change in use patterns from one of occasional use to one of compulsive drug-taking behavior and addiction. The neurochemical and neuropharmacological processes that occur during the transition from acute drug action to the development of tolerance and addiction can provide important insights into mechanisms that may facilitate the management of pain and reduce addiction liability. Our hypothesis is that the transition from the acute pharmacological effects of morphine to tolerance and dependence is caused by large-scale changes in gene expression. The purpose of this grant is to utilize large-scale gene expression profiles to identify changes in gene expression directly related to the behavioral effects of acute and chronic opioid administration. The experiments are specifically designed to identify functionally relevant changes in gene expression by using a behavior genetics 'filter' to weed out expression changes unrelated to specific behavioral endpoints. The specific aims are to 1) Characterize the analgesic and reinforcing effects of acute and chronic morphine administration in a number of inbred and genetically engineered genotypes that show qualitative and quantitative differences in antinociceptive tolerance and drug self-administration behavior; 2) Identify regional patterns of gene expression in mice following acute and chronic morphine administration and 3) Use structured statistical analysis to identify significant alterations in gene expression within each genotype and then use correlative analysis to specifically relate changes in gene expression patterns to the genotype-specific behavioral effects of morphine. By specifically relating gene expression profiles to genotype-dependent differences in the behavioral effects of morphine we hope to identify functionally relevant candidate genes and gene products useful for therapeutic intervention in reduced analgesic efficacy and drug abuse liability following chronic exposure to opioids.

描述（由申请方提供）：阿片类药物产生对疼痛治疗有价值的急性药理作用。急性阿片类药物给药也会在娱乐性药物使用者中产生欣快状态。然而，重复阿片类药物给药可导致镇痛疗效进行性下降，使用模式从偶尔使用变为强迫性吸毒行为和成瘾。在从急性药物作用到耐受性和成瘾发展的过渡期间发生的神经化学和神经药理学过程可以为可能促进疼痛管理和减少成瘾倾向的机制提供重要的见解。我们的假设是，从吗啡的急性药理作用的耐受性和依赖性的转变是由基因表达的大规模变化。这项资助的目的是利用大规模的基因表达谱来识别与急性和慢性阿片类药物给药的行为效应直接相关的基因表达变化。这些实验是专门设计的，通过使用行为遗传学“过滤器”来清除与特定行为终点无关的表达变化，以识别基因表达的功能相关变化。具体目的是1）表征急性和慢性吗啡给药在许多近交和遗传工程基因型中的镇痛和增强作用，所述基因型在抗伤害性耐受和药物自我给药行为中显示出定性和定量差异; 2）确定急性和慢性吗啡给药后小鼠中基因表达的区域模式，以及3）使用结构化的统计分析，以确定每个基因型内的基因表达的显着变化，然后使用相关性分析，以具体地将基因表达模式的变化与吗啡的基因型特异性行为效应。通过特异性地将基因表达谱与吗啡行为效应的基因型依赖性差异相关联，我们希望能够鉴定出功能相关的候选基因和基因产物，这些基因和基因产物可用于治疗性干预慢性阿片类药物暴露后镇痛效果降低和药物滥用倾向。