Opioids And Cellular Survival

National Institute On Drug Abuse

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Abstract

This project examines the physiological effects and the underlying biochemical mechanisms of the action of delta opioid peptide DADLE in cellular survival. Three main discoveries are made this year. The first two are from collaborative studies with extramural scientists. The third is from our own laboratory. (1)DADLE confers myocardial tolerance to ischemia in isolated rabbit hearts by activating delta-2 opioid receptors. While control hearts exhibit a shrinkage of mitochondria and a loss of striatal structure, the DADLE-treated hearts are apparently normal. (2) In a study using isolated rat hearts, it was found that the myocardial protection by means of ischemic preconditioning involves the activation of delta opioid systems. Delta opioid antagonist blocks the myocardial protection via ischemic preconditioning. (3) Using PC12 cells in culture, we found that DADLE is neuroprotective only in very low concentrations (femto molar). In higher concentrations in the micromolar range, however, DADLE induces cell death. The neuroprotective effect of DADLE involves the DADLE's ability to induce the phosphorylation of ERK which is related to the cellular survival pathway inside the cell. The cytotoxic effect of DADLE is due to its ability to cause an increase of a death ligand called Fas-ligand. Further, we found that, similar to that observed in isolated rabbit hearts, DADLE's protecitve effect in PC12 cells is also through delta-2 opioid receptors. The cytotoxic effect of DADLE, when used in high concentrations, is through its ability to activate mu subtype of opioid receptors.