Opiate modulating properties of the Tyr-MIF-1 family of endogenous peptides: From whole animal to subcellular levels
Description
The mechanism of action of the Tyr-MIF-1 family of antiopiate peptides and their possible role in opiate tolerance was investigated at several levels: whole animal, cellular, and subcellular. At the whole animal level, it was demonstrated that Tyr-MIF-1 potentiates, rather than attenuates, some effects of chronic opiate administration to neonatal rats. Chronic neonatal morphine decreased pup body weight, and this effect was slightly potentiated by Tyr-MIF-1. Chronic morphine also affected the blood-brain barrier transport system PTS-1 (peptide transport system-1), which transports Met-enkephalin and Tyr-MIF-1 in the brain to blood direction. The transport was increased by neonatal morphine, and this effect was significantly potentiated by Tyr-MIF-1. In a cellular model system, SH-SY5Y human neuroblastoma cells, the related peptide Tyr-W-MIF-1 displayed opiate antagonist properties. This peptide dose-dependently attenuated the down-regulation of opiate receptors induced by chronic agonist treatment. This result suggests a mechanism whereby this peptide can participate in tolerance by counteracting the effects of chronic opiate administration at the receptor level. Finally, the mechanism of dual agonist/antagonist properties by a single peptide was investigated in SH-SY5Y membranes. Activation by Tyr-W-MIF-1 of G-proteins, the first step in signal transduction after binding to a receptor, was measured and compared to the activation induced by other opiate ligands. Depending on the assay conditions, Tyr-W-MIF-1 could either stimulate or inhibit G-protein activation. In the absence of added dithiothreitol (DTT), a sulfhydryl reducing agent, the peptide inhibited basal G-protein activation. However, in the presence of added DTT, the peptide did not inhibit activation of G-proteins and instead showed a small activation. Thus, under different tissue conditions, a single peptide can show opposite effects on G-protein, which could, in turn, result in opposite physiological effects. These results suggest a mechanism at the subcellular level for the dual agonist/antagonist properties of Tyr-MIF-1 peptides