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.
