Role of opioid receptor heterodimerization in pain modulation and tolerance development

Figure 1 Anti-opioid model for tolerance and physical dependence.

Figure 2 Dualsteric ligand mediated activation of the heteromer.

Figure 3 Dualsteric ligand induced regulation of opioid receptors heteromer. Without agonist treatment, about 15% of the receptors are intracellular and G protein trimers are associated with each other with GDP bound to Gα subunits. Upon exposure to agonist, the receptor is activated and coupled to G proteins, triggering the exchange of GDP with GTP and dissociation of Gα from Gβγ subunits, which in turn activate down-stream effectors. Activation of the receptor also causes translocation and activation of GRKs, which phosphorylated the receptor in intracellular domains. Receptor phosphorylation enhances binding of β-arrestins, leading to uncoupling of receptors from G proteins. β-arrestins bind to clathrin and initiate movement of receptors into clathrin-coated pits, which are pinched by dynamin to become endosomes. Low pH in endosomes facilitates dissociation of agonists from the receptor and dephosphorylation of the receptor is believed to occur here. Internalized receptors are routed to two different pathways. Some are sorted to recycling endosomes and returned to plasma membranes. Alternatively, the receptors lead to degradation forming lysosomes. GRK: G-protein coupled receptor kinase; GDP: Guanosine-5'-diphosphate; GTP: Guanosine-5'-triphosphate.

Figure 4 Hypothesis about the role of receptor internalization in the development of opioid tolerance. A: In the presence of “non-internalizing” opioids, exemplified by morphine, receptor signaling is rapidly terminated by receptor phosphorylation and β-arrestin binding. The desensitized receptors remain inactivated in the plasma membrane leading to signaling desensitization and opioid tolerance; B: In contrast, “internalizing” opioids such as DAMGO [D-Ala2, N-MePhe4, Gly-ol]-enkephalin lead to receptor desensitization by phosphorylation and β-arrestin binding but also to rapid receptor internalization and resensitization counteracting signaling desensitization and opioid tolerance.