Differential regulation of the μ-opioid receptor (MOR), a G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptor, contributes to the clinically limiting effects of opioid analgesics, such as morphine. Different MOR agonists produce different biological effects, in part by differentially regulating receptor phosphorylation and internalization.
In cells transfected with MOR, researchers. examined downstream signaling in the absence of receptor internalization. Whereas the synthetic opioid DAMGO stimulated receptor movement within the plasma membrane, transiently increased ERK activity in both the cytosol and nucleus and receptor internalization.
Morphine stimulated a protein kinase C–dependent pathway that restricted MOR movement and transient increase in cytosolic and nuclear ERK activity without receptor internalization.
Similar effects were observed in mouse dorsal root ganglion neurons, suggesting that the differences in plasma membrane mobility or clustering of MOR may underlie the differential effects of its agonists in vivo.