Microarray analysis of morphine's behavioral effects

描述(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。急性阿片类药物使用也会使娱乐吸毒者处于一种愉悦的状态。然而，反复使用阿片类药物会导致止痛效果的进行性下降，并导致使用模式从偶尔使用转变为强制服药行为和成瘾。在从急性药物作用到耐受性和成瘾发展的过渡过程中发生的神经化学和神经药理学过程可以为有助于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。这笔赠款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。这些实验是专门为识别基因表达的功能相关变化而设计的，方法是使用行为遗传学“过滤器”来剔除与特定行为终点无关的表达变化。其具体目标是1)在一些近交系和基因工程基因型中表征急性和长期服用吗啡的镇痛和增强效果，这些基因型在抗伤害耐受性和药物自我给药行为方面显示出质和量上的差异；2)确定急性和慢性服用吗啡后小鼠基因表达的区域模式；3)使用结构化统计分析来确定每个基因型内基因表达的显著变化，然后使用相关分析将基因表达模式的变化与吗啡特定基因型的行为效应具体关联起来。通过明确地将基因表达谱与吗啡行为效应的基因型相关差异联系起来，我们希望找出功能相关的候选基因和基因产品，用于治疗阿片类药物慢性暴露后镇痛效果和药物滥用易感性的降低。

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.