Role of opioid receptor heterodimerization in pain modulation and tolerance development

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.