Opioid receptors belong to the G protein-coupled receptor (GPCR) family, characterized by a seven-transmembrane span structure. Opioid receptors are expressed on primary sensory neurons in pain-modulating descending pathways, which include the medulla, locus coeruleus, and periaqueductal gray area. A key feature of opioid ligands is that they show varying affinity for the different opioid receptors and their subtypes. The same ligand can induce differential signaling profiles when a receptor is expressed in different cell types. All opiate agonists can induce tolerance and dependence if administered at high enough doses for a long enough time. Three pharmacological types of opioid receptors, MOR, DOR and KOR have been identified. A fourth opioid receptor, ORL1, is genetically closely related to the others. These receptors are about 60% identical, with the strongest similarity found in the transmembrane domains (73-76%) and intracellular loops (86-100%).
Opioid receptors mediate many of their cellular effects via activation of heterotrimeric pertussis toxin-sensitive G-proteins (Gαβγ). The association of GTP with the Gα subunit of the heterotrimer results in the generation of two signaling molecules, Gα and Gβγ, which activate different effector systems. Adenylyl cyclase (AC) is an important effector of Gα. Acutely, opioid agonists inhibit AC activity, but after chronic opioid treatment the AC level increases, which results in the synthesis of cAMP and resumed activation of its signaling pathway. Chronic up-regulation of cAMP and depolarization of the neuronal membrane potential are associated with opioid tolerance and dependence.
Gβγ subunit has more effectors than Gα, including G protein-gated inwardly rectifying K channels (GIRK), voltage-dependent calcium channels (VDCC), G protein-coupled receptor kinase (GRKs), phospholipase C (PLC), AC, and others. Gβγ subunits also stimulate proliferation via mitogen activated protein kinase (MAPK) cascade and promote cell survival by the activation of phosphotidylinositol-3-kinase (PI3K). The overall action of opioid drugs is to inhibit neurotransmitter release by inhibiting the VDCCs and activating the GIRKs, which are involved in preventing neuronal excitation / action potential propagation. Activation of Erk1/2 through the Gβγ subunit and in a Ras-dependent manner has been linked to cell survival and proliferation.
Binding of opioid agonists results in the rapid phosphorylation of the receptor by different protein kinases, including the G protein-coupled receptor kinases (GRKs) and second messenger-regulated kinases (PKC, PKA, CaMK). GRKs promote the association of the cellular protein β-arrestin, which is involved in the agonist-induced, clathrin-coated vesicle-mediated receptor internalization. Association of β-arrestin with the receptor uncouples the receptor from the respective G protein, blunting receptor signaling and promoting desensitization. Not all types of agonist can induce receptor internalization. For example, morphine only induces slight or no internalization of MOR, whereas agonists with high efficacy such as DAMGO induce rapid and significant internalization of MOR. The reduction of receptor quantity and/or inactivation of receptor protein by protein kinases during chronic treatment can lead to opioid tolerance and dependence.
Localization of receptors is not static and may vary considerably with activity and other conditions. Internalized receptors can resensitize and recycle back to the cell surface where receptor signaling is continued, or trafficking can be directed to other subcellular compartments, such as lysosomes, for degradation.