The primary goal of this project is the development of an understanding of the mechanisms by which activation of opioid receptors regulates neuronal or endocrine cell function, and of the consequences at a molecular level of the effects of chronic opioid exposure. In the first set of proposed studies, emphasis will be given to interactions of opiate drugs with mu- type opioid receptors since most clinically used or abused opioids have selectivity for this opioid receptor class. Studies initiated in the current grant period utilizing the 7315c pituitary tumor cell, which carries a homogenous population of mu-class of opioid receptors, will be continued. A comparison will be made of the effects on mu-receptor function of morphine and other agents including full agonists (etorphine and Tyr-D-Ala-Gly-N(Me)Phe-Gly-ol) and partial agonists (buprenorphine, pentazocine). A more detailed study at a biochemical level of the effects of buprenorphine is required in view of the increasing interest in the use of this drug in the treatment of opiate drug addiction. The effects of chronic morphine exposure on the functional activity of G-proteins and on the turnover of opioid receptors will also be evaluated. A second part of the project will be concerned with the evaluation of possible k-type opioid receptor heterogeneity in neural tissues, and with the development of in vitro cell systems which can be used to examine the consequences of k-type receptor activation as NG 108-15 cells have been used to study delta- receptor function and 7315c cells to study mu-receptor function. The use of guinea pig cerebellar cells in primary cultures, and after fusion with neuroblastoma cells without opioid receptors, will be evaluated initially since guinea pig cerebellum has been shown to be very enriched in opioid receptors of the k-type. Other sources of k-receptor will be employed if use of guinea pig cerebellar cells becomes impracticable. In another set of studies, the acute and chronic effects of opioids on the release of norepinephrine and dopamine from defined neural pathways in rat and guinea pig will be examined. Both brain slices preparations will be studied. These studies are of significance since inhibition of neurotransmitter release appears to be an important mechanism underlying the effects of opioids on pain perception and mood.
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