Previous in vitro studies that examined how the A118G polymorphism affected signaling mechanisms and receptor function relied on the heterologous expression of the receptors. Some of the reported observations indicated that the results were affected by cell type and transfection method employed17,19,37. The advantage of the humanized mouse model used in our study is that the underlying mechanisms of the opiate inter-variability observed clinically can be investigated directly in cells from tissue that is involved in pain transmission.