The role of opioid receptor internalization and beta-arrestins in the development of opioid tolerance

Anesth Analg. 2005 Sep;101(3):728-734. doi: 10.1213/01.ANE.0000160588.32007.AD.


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 beta-arrestins in opioid receptor desensitization and internalization and opioid tolerance. Although beta-arrestin 1 and beta-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 beta-arrestin 2. Modification of opioid receptor internalization by affecting the interaction between opioid receptors and beta-arrestins may be a therapeutic target for reducing opioid tolerance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Analgesics, Opioid / pharmacology*
  • Arrestin / physiology*
  • Drug Tolerance
  • Humans
  • Receptors, Opioid / drug effects
  • Receptors, Opioid / physiology*
  • Signal Transduction / physiology


  • Analgesics, Opioid
  • Arrestin
  • Receptors, Opioid