Microarray analysis of morphine's behavioral effects

描述（由申请人提供）：阿片类药物产生对治疗疼痛有价值的急性药理作用。急性阿片类药物也能使娱乐性药物使用者产生欣快状态。然而，反复服用阿片类药物会导致镇痛效果的逐渐下降，并导致使用模式的改变，从偶尔使用到强迫性吸毒行为和成瘾。从急性药物作用到耐受性和成瘾的转变过程中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责任的机制提供重要见解。我们的假设是，从吗啡的急性药理作用到耐受和依赖的转变是由基因表达的大规模变化引起的。这项资助的目的是利用大规模的基因表达谱来确定与急性和慢性阿片类药物给药的行为影响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”来剔除与特定行为端点无关的表达变化，从而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的镇痛和强化作用在一些自交系和基因工程基因型中表现出抗痛感耐受性和药物自我给药行为的定性和定量差异；2)确定急性和慢性吗啡给药小鼠基因表达的区域模式；3)利用结构化统计分析确定各基因型内基因表达的显著变化，然后利用相关分析特异性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联系起来。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差异联系起来，我们希望确定功能相关的候选基因和基因产物，这些基因和基因产物对慢性阿片类药物暴露后镇痛效果降低和药物滥用倾向的治疗干预有用。

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.