Like the extracellular domains, differences in the intracellular regions allow for specificity of downstream signaling and account for the different pathways activated by the three receptor types. The intracellular domains interact with heterotrimeric Gi/G0 proteins, which are released as the α and βγ subunits following receptor activation. The release of the G protein subunits results in altered ion channel activity and decreased membrane potential, as well as activation of MAPK pathways leading to changes in gene expression (reviewed in [1]). Despite the similar mechanisms, the differences in the intracellular domains of MOR, DOR, and KOR result in different phenotypes when the receptors are activated. Activation of MOR or DOR results in rewarding effects and analgesia, while KOR is involved in aversion and dysphoria. Opioid receptor heterodimers also occur in vivo and have been shown to regulate unique phenotypes that differ from those regulated by the individual receptor types, adding further complexity to opioid receptor signaling (reviewed in [2]).
