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.
