Analysis of Morphine Induced Behavioral Effects

描述（由申请方提供）：本申请旨在鉴定与神经化学和神经药理学过程相关的基因表达的功能相关变化，这些过程发生在从急性药物作用到耐受性发展的过渡过程中。通过使用行为遗传学过滤器拒绝与表明耐受性的特定行为终点无关的表达变化来识别基因表达中的功能相关变化的实验将检验以下假设：从吗啡的急性效应到耐受性的过渡是由基因表达中的大规模变化引起的。为了实现这一目标，吗啡将被给予一些近交系小鼠品系，其中一些表现出耐受性，而另一些则没有发展出耐受性。吗啡诱导的基因表达变化将与这些基因型之间的行为差异相关。例如，如果一个特定的基因在表现出耐受性的基因型和那些没有表现出耐受性的基因型中表现出增加的表达水平，则该特定基因不太可能与耐受性所涉及的神经化学机制相关。如果一个特定的基因只在表现出耐受性的基因型中表现出改变的表达，那么该基因可能与耐受性所涉及的神经化学机制有关。以这种方式，只有那些与神经化学或行为终点特异性相关的基因或基因簇才被鉴定为候选基因。这种方法使我们能够具体地将基因表达谱与吗啡的行为表型效应中的基因型依赖性差异联系起来。这将允许鉴定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，以降低慢性阿片类药物暴露后的镇痛疗效和药物滥用倾向。

DESCRIPTION (provided by applicant): This application aims to identify functionally relevant changes in gene expression involved with the neurochemical and neuropharmacological processes that occur in the transition from acute drug action to the development of tolerance. Experiments to identify functionally relevant changes in gene expression by using a behavioral genetics filter to reject expression changes unrelated to the specific behavioral endpoint indicating tolerance will test the hypothesis that the transition from the acute effects of morphine to tolerance results from a large-scale change in gene expression. To accomplish this goal, morphine will be given to a number of inbred mouse strains, some of which show tolerance and others that do not develop tolerance. Morphine-induced changes in gene expression will then be correlated with behavioral differences found across these genotypes. For example, if a particular gene shows increased expression levels in genotypes that show tolerance and those that do not, that particular gene is not likely related to neurochemical mechanisms involved in tolerance. If a particular gene shows altered expression only in genotypes that show tolerance then that gene is likely related to the neurochemical mechanisms involved in tolerance. In this manner, only those genes or gene clusters specifically related to a neurochemical or behavioral endpoint will be identified as candidate genes. This approach allows us to specifically relate gene expression profiles to genotype dependent differences in the behavioral phenotypic effects of morphine. This will allow identification of functionally relevant candidate genes and gene products that could be useful in therapeutic intervention in reduced analgesic efficacy and drug abuse liability following chronic opioid exposure.