only species-specific but also context-specific mechanisms in the modulation of MOR signaling. For example, overexpression studies were primarily done in cell models in order to elucidate differences in signaling pathways relevant to the human condition. However, it is also possible that this “gain of function” effect of MOR N40D observed in overexpression systems is an artifact of an increased receptor density at the cell surface and not due to true differences in signaling efficacy from MOR N40D, suggesting the need for a model system that recapitulates proper receptor expression levels. Moreover, it is possible that the “loss-of-function” phenotype observed in the A112G and A118G humanized mouse models are likely a consequence of rodent-specific regulation in receptor expression levels. Both these results necessitate the need for a human neuronal model to elucidate the appropriate mechanisms, which would represent endogenous levels of MOR in a disease-relevant cell type.
