Opioid receptors are part of the Rhodopsin family of G-protein coupled receptors (GPCRs), which activate downstream signaling through interactions with heterotrimeric G proteins. The three most common types are the μ-opioid receptor (MOR), δ-opioid receptor (DOR), and κ-opioid receptor (KOR), encoded by the OPRM1, OPRD1, and OPRK1 genes, respectively. Each receptor type has seven transmembrane domains, three intracellular loops, three extracellular loops, an extracellular N-terminus, and an intracellular C-terminus. The three main receptor types are highly homologous within the transmembrane domains, which are arranged in a helical pattern, but have significantly less homology in the extracellular regions. Key residues within these domains create a ligand-binding pocket and binding of opioid agonists within the pocket results in activation of the opioid receptor and subsequent downstream signaling. Variation in the extracellular loops regulates ligandreceptor interaction and allows varying degrees of specificity between different endogenous peptides and opioid receptor types. MOR is activated by both endomorphins and β-endorphin, a cleavage product of the proopiomelanocortin precursor. Enkephalin and deltorphin have been shown to activate DOR, while the dynorphin class of peptides is specific for the KOR protein. Many of these peptides have some affinity for more than one receptor type.
