The Role of Opioid Receptor Internalization and ??-Arrestins in the Development of Opioid Tolerance

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Abstract
Opioid tolerance, a phenomenon characterized by decreased analgesic effects obtained by the same dose of opioids after repeated use of the opioids, is a significant clinical problem. Traditional theory attributes receptor desensitization and internalization and post-receptor adaptation to the development of opioid tolerance. However, morphine, a commonly used opioid, induces tolerance but is not an effective drug to induce opioid receptor desensitization and internalization. Recent studies found that internalized opioid receptors can become competent receptors and recycle back to the cell surface membrane after dephosphorylation. Thus, receptor internalization may be a way to reduce opioid tolerance. Multiple studies have suggested a key role of β-arrestins in opioid receptor desensitization and internalization and opioid tolerance. Although β-arrestin 1 and β-arrestin 2 are important for these effects induced by opioids with high intrinsic efficacy such as etorphine and fentanyl, morphine tolerance may be mediated mainly via β-arrestin 2. Modification of opioid receptor internalization by affecting the interaction between opioid receptors and β-arrestins may be a therapeutic target for reducing opioid tolerance.