Biased agonism and opioid receptor-mediated analgesia

抄録

We have investigated how the nature of ligands binding to opioid receptors can differentially effect the receptor's ability to signal in different pathways and how this translates to differential physiological outcomes. Towards this goal, we have made a series of compound that display a spectrum of biased agonism. Relative to the enkephalin analog, DAMGO, some are more efficient at promoting beta-arrestin recruitment over G protein while several are progressively more more effective at promoting G protein signaling over promoting beta-arrestin interactions. We have then assured that all of the compound have pharmacokinetic properties in mice that assure comparable (if not greater) exposure than obtained with morphine. Finally, we have assessed their potencies for producing antinociception and alterations in respiratory parameters in mice. We find that increasing the degree of biased agonism produces an improved therapeutic window. I will share data regarding how biased agonism impacts upon antinociceptive tolerance development in mice. This work has been funded by NIDA/NIH (R01DA033073 and R01DA38964).