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The opioid system has already been shown to be an intricate one containing at least three receptors and three endogenous ligand precursors. Our lab has recently constructed strains of mice with deletions of several of the genes in the opioid system and thus has several genetic models in which to study the intricacices of the system. Although no apparent morphologic alteration results from any of these mutations, both predicted and unexpected behavioral changes have been found to arise from each mutation. For example the delta opioid receptor-1 (DOR-1) gene null mice a retain intracerebroventricular (icv) DPDPE (a traditional DOR ligand) analgesia and lack tolerance to chronic treatment with morphine. The focus of this project is to evaluate functional receptor changes that accompany the deletion of the DOR-1 gene. Briefly, the regulation of gene expression and receptor function in this mouse will be explored. GTP-gamma- 35S binding studies will be done to see if deletion of the delta opioid receptor gene (DOR-1) produces compensatory changes in receptor function in early development as well as in the adult. In addition, the neuropharmacology and anatomical site of action of retained icv DPDPE analgesia in these mice will be clarified. Competitive binding experiments along with GTP-gamma-35S binding experiments will be done to determine DPDPE's neuropharmacology in the DOR-1 mice. In addition, the anatomical distribution of DPDPE activity in the DOR-1 null mouse will be mapped using GTP- gamma-35S autoradiography. If time permits, mRNA will be extracted from brain areas with high DPDPE activity, a cDNA library will be constructed, and the gene mediating DPDPE analgesi will be cloned using functional expression. Finally, the effect of DOR-1 ablation on the functional receptor changes associated with chronic morphine exposure will be explored, GTP- gamma-35S binding studies will again be used to see whether DOR-1 mutation effects coupling changes previously seen in the periaqueductal gray and the nucleus tractus solitarius after prolonged exposure to morphine.
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