The role of mu opioid receptor desensitization and endocytosis in morphine tolerance and dependence

  title={The role of mu opioid receptor desensitization and endocytosis in morphine tolerance and dependence},
  author={Lene Martini and Jennifer L. Whistler},
  journal={Current Opinion in Neurobiology},

Fast Modulation of μ-Opioid Receptor (MOR) Recycling Is Mediated by Receptor Agonists*

This work identifies a novel trafficking mechanism that increases the number of cell surface MORs during acute agonist exposure, effectively reducing the development of opioid tolerance.

Ligand-Selective Receptor Desensitization and Endocytosis

This chapter outlines several cases in which ligands show functional selectivity for receptor trafficking with an emphasis on receptors in which altered ligand-induced trafficking has been shown to be relevant to human disease.

Quantitative Encoding of the Effect of a Partial Agonist on Individual Opioid Receptors by Multisite Phosphorylation and Threshold Detection

Quantitatively, however, the different agonists promoted disproportionate multisite phosphorylation of a specific serine and threonine motif, and it was found that modification at more than one residue was essential for the efficient recruitment of the adaptor protein β-arrestin that mediated subsequent endocytosis of MORs.

Regulation of µ-Opioid Receptors: Desensitization, Phosphorylation, Internalization, and Tolerance

There are large gaps in understanding the molecular processes responsible for loss of MOR function after chronic exposure to opioids, and further elucidation of the cellular mechanisms that are regulated by opioids will be necessary for the successful development of MOR-based approaches to new pain therapeutics that limit the development of tolerance.

Regulation of Mu Opioid Receptor Trafficking, Signaling, and Recycling in Neurons

A novel function of sequence-directed recycling is identified in mediating rapid local delivery of signaling receptors to the somatodendritic plasma membrane in neurons using endogenous MORs expressed in multipleneuronal populations.

Mechanisms of rapid opioid receptor desensitization, resensitization and tolerance in brain neurons

This review will examine notions based on dogma that β‐arrestin‐2 (βarr‐2) binding causes MOR desensitization and/or that MOR endocytosis and recycling are required for receptor resensItization in light of recent evidence establishing that MOR dephosphorylation and resensitizing do not require endocyTosis.

Bidirectional Effects of Fentanyl on Dendritic Spines and AMPA Receptors Depend Upon the Internalization of Mu Opioid Receptors

The blockade of receptor internalization with the expression of dominant-negative Dynamin I (the K44E mutant) reversed the effect of fentanyl at high concentrations, supporting a role of receptorinternalization in modulating the dose-dependent effects of fentanyl.

μ-Opioid Receptors: Correlation of Agonist Efficacy for Signalling with Ability to Activate Internalization

Data indicate that for the majority of MOPr agonists the ability to induce receptor phosphorylation, arrestin-3 recruitment, and internalization can be predicted from their ability as agonists to activate G proteins.

Functional Selectivity at Opioid Receptors

Evidence supporting the existence of ligand-selective conformations for μ and δ-opioid receptors is summarized and how functional selectivity may contribute to the production of longer lasting, better tolerated opiate analgesics is analyzed.



μ-Opioid Receptors: Ligand-Dependent Activation of Potassium Conductance, Desensitization, and Internalization

The results suggest that agonist efficacy is not necessarily a predictor of the ability to cause MOR desensitization or endocytosis, and identification and characterization of the biophysical properties of agonists that favor desens itization and internalization of receptors will lead to a better understanding of opioid signaling.

Agonist-selective endocytosis of mu opioid receptor by neurons in vivo.

  • C. SterniniM. Spann N. Brecha
  • Biology, Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 1996
The occurrence of agonist-selective MOR endocytosis in neurons naturally expressing this receptor in vivo is demonstrated and the existence of different mechanisms regulating cellular responsiveness to ligands is suggested.

Receptor Endocytosis Counteracts the Development of Opioid Tolerance

It is demonstrated that the endocytotic potencies of opioid drugs are negatively correlated with their ability to cause receptor desensitization and opioid tolerance in HEK 293 cells, and shown that agonist-induced receptor endocytic facilitates the compensatory up-regulation of the cAMP pathway, a cellular hallmark of opioid withdrawal.

Role for G protein-coupled receptor kinase in agonist-specific regulation of mu-opioid receptor responsiveness.

It is reported that the ability of distinct opioid agonists to differentially regulate mu OR internalization and desensitization is related to their ability to promote G protein-coupled receptor kinase (GRK)-dependent phosphorylation of the mu OR.

mu-Opioid receptor internalization: opiate drugs have differential effects on a conserved endocytic mechanism in vitro and in the mammalian brain.

The studies indicated that the different effects of individual agonists are not correlated with their potencies for receptor activation and that a variety of clinically important agonists differ significantly in their relative abilities to stimulate the rapid internalization of opioid receptors.

Enhancement of Morphine Analgesic Effect with Induction of &mgr;-Opioid Receptor Endocytosis in Rats

The results suggest that the coadministration of morphine with MOR-internalizing agonist is clinically applicable to develop successful pain-management regimens to achieve satisfactory analgesia using less morphine.

Morphine Activates Opioid Receptors without Causing Their Rapid Internalization*

The data indicate that agonist ligands, which have similar effects on receptor-mediated signaling, can have dramatically different effects on the intracellular trafficking of a G protein-coupled receptor.

Morphine induces endocytosis of neuronal μ-opioid receptors through the sustained transfer of Gα subunits to RGSZ2 proteins

In the nervous system, morphine induces a strong desensitization before promoting the phosphorylation and recycling of MORs, and recycled MORs recover the control on these Gα subunits and opioid tolerance develops slowly.

Morphine Promotes Rapid, Arrestin-Dependent Endocytosis of μ-Opioid Receptors in Striatal Neurons

It is indicated that morphine is indeed capable of driving rapid endocytosis of μ-opioid receptors in an important subset of opiate-responsive CNS neurons, and a cellular mechanism by which β-arrestins may modulate the physiological effects of morphine in vivo is suggested.

μ-Opioid Receptor Desensitization in Mature Rat Neurons: Lack of Interaction between DAMGO and Morphine

The data presented here fail to support the theory that low concentrations of DAMGO can increase morphine-induced MOR desensitization or internalization.