Associate editor: K. RackéRole of receptor internalization in opioid tolerance and dependence
Introduction
Opioid receptors belong to the superfamily of seven transmembrane receptors and produce their cellular effects via coupling with pertussis toxin-sensitive GTP-binding proteins Gi/Go. Activation of opioid receptors leads to neuronal inhibition caused by multiple effectors, including inhibition of intracellular cAMP production and voltage gated Ca2+channels, as well as the stimulation of inwardly rectifying K+ channels (Law et al., 2000b). Opioids are the most commonly used analgesics but their clinical use is limited by the development of tolerance and physical dependence. The molecular mechanisms underlying the development of opioid tolerance and dependence remain unclear. In vitro and in vivo studies revealed that on the cellular level chronic opioid treatment leads to a rapid reduction of agonist response accompanied by internalization of receptors. These early adaptive processes as well as long-term adaptations such as receptor downregulation, or counterregulatory processes such as adenylate cyclase superactivation have been suggested to be crucial to the development of opioid tolerance (Ferguson, 2001, von Zastrow et al., 2003, Bailey and Connor, 2005). An important step resulting in MOPr desensitization is the phosphorylation of intracellular receptor domains by G-protein coupled receptor kinases and/or second messenger-regulated protein kinases (Harada et al., 1990, Mestek et al., 1995, Koch et al., 1997, Kovoor et al., 1998, Polakiewicz et al., 1998, Schmidt et al., 2000, Johnson et al., 2006). After phosphorylation of the receptor, β-arrestins are recruited to the plasma membrane where they accelerate uncoupling of the receptor from the G-protein and facilitate receptor internalization by serving as scaffolding proteins that bind to clathrin (Ferguson et al., 1996, Goodman et al., 1996). Remarkably, there are important differences in the phosphorylation, desensitization and subsequent internalization of opioid receptors between various opioid agonists (Alvarez et al., 2002, Schulz et al., 2004, Koch et al., 2005, Johnson et al., 2006). Recent publications further implicated that the relative activity of certain opioid drugs to induce regulatory endocytosis of receptors appears to be inversely correlated with the ability of these drugs to induce opioid tolerance (Koch et al., 1998, Koch et al., 2005, Whistler et al., 1999). These findings gave rise to the RA/VE-theory assuming that agonist activity and receptor endocytosis have opposite effects on receptor signaling and that the net amount of signaling transmitted to the cell is a function of both processes, a relationship termed RA/VE for relative activity versus endocytosis (Whistler et al., 1999, Finn and Whistler, 2001). According to the RA/VE model, MOPr agonists with low RA/VE values, like DAMGO or methadone, might induce less opioid tolerance than those with high RA/VE values, such as morphine (He et al., 2002, He and Whistler, 2005). Thus, there is experimental evidence to suggets that agonist-mediated regulation of the MOPr internalization and trafficking might play a critical role in the development of opioid tolerance and dependence. The purpose of this article is to review the literature concerning the role of receptor internalization within the regulation of receptor activity and cellular and molecular adaptations resulting from chronic opioid exposure.
Section snippets
Opioid receptor phosphorylation and uncoupling
Desensitization is defined as the progressive loss of receptor function under continued exposure to an agonist. Receptor phosphorylation is thought to be the key initial event for acute receptor desensitization. In support of this suggestion it has been demonstrated that prolonged opioid exposure resulted in an increased MOPr phosphorylation in transfected CHO cells (Zhang et al., 1996) and HEK293 cells (Arden et al., 1995, Schulz et al., 2004) but also in MOPr expressing neuronal cells (Deng
Mechanisms involved in the reduction of opioid tolerance by receptor internalization
Several lines of evidence indicate that agonist-induced MOPr endocytosis can reduce the development of opioid tolerance (Koch et al., 1998, Koch et al., 2004, Koch et al., 2006, Whistler and von Zastrow, 1999, Law et al., 2000a, He et al., 2002, He and Whistler, 2005, Grecksch et al., 2006) but the mechanisms that are responsible for the protection against opioid tolerance by receptor endocytosis are still controversially discussed. One hypothesis is that MOPr endocytosis terminates signaling
Summary
It is now evident, that the development of opioid tolerance is dependent not only on receptor phosphorylation and uncoupling, or long-term adaptations, such as upregulation of the cAMP-pathway, but also on the agonist-selective MOPr internalization. Receptor internalization has long been considered to directly contribute to the development of opioid tolerance by reducing the number of signaling receptors. However, several lines of evidence indicate that receptor internalization might provide an
References (115)
- et al.
Chronic opioid treatment induces adenylyl cyclase V superactivation. Involvement of Gβ
J Biol Chem
(1996) - et al.
Opioids: cellular mechanisms of tolerance and physical dependence
Curr Opin Pharmacol
(2005) - et al.
Two distinct forms of desensitization of G-protein coupled inwardly rectifying potassium currents evoked by alkaloid and peptide μ-opioid receptor agonists
Mol Cell Neurosci
(2003) - et al.
Opioid agonists have different efficacy profiles for G protein activation, rapid desensitization, and endocytosis of μ-opioid receptors
J Biol Chem
(2003) - et al.
Chronic morphine increase μ-opioid receptor binding in rat brain: a quantitative autoradiographic study
Brain Res
(1989) - et al.
Magnitude of tolerance to fentanyl is independent of mu-opioid receptor density
Eur J Pharmacol
(1997) - et al.
Internalization and recycling of human μ-opioid receptors expressed in Sf9 insect cells
Life Sci
(2003) - et al.
Differential regulation by cAMP-dependent protein kinase and protein kinase C of the μ-opioid receptor coupling to a G protein-activated K+channel
J Biol Chem
(1994) - et al.
Phospholipase D2, a distinct phospholipase D isoform with novel regulatory properties that provokes cytoskeletal reorganization
Curr Biol
(1997) - et al.
Dimerization of the delta opioid receptor: implication for a role in receptor internalization
J Biol Chem
(1997)
Agonist-induced mu opioid receptor phosphorylation and functional desensitization in rat thalamus
Brain Res
Down-regulation of δ-but not μ-opioid receptors in the hippocampal slice associated with loss of physiological response
Life Sci
Phosphorylation of Ser363, Thr370, and Ser375 residues within the carboxyl tail differentially regulates μ-opioid receptor internalization
J Biol Chem
The absence of a direct correlation between the loss of [D-Ala2, MePhe4,Gly5-ol]Enkephalin inhibition of adenylyl cyclase activity and agonist-induced mu-opioid receptor phosphorylation
J Biol Chem
G protein-coupled receptor adaptation mechanisms
Semin Cell Dev Biol
Molecular mechanisms of G protein-coupled receptor desensitization and resensitization
Life Sci
μ-Opioid receptor down-regulation and tolerance are not equally dependent upon G-protein signaling
Pharmacol Biochem Behav
Phosphorylated mu-receptor purified from rat brains lacks functional coupling with Gi1, a GTP-binding protein in reconstituted lipid vesicles
Neurosci Lett
An opiate cocktail that reduces morphine tolerance and dependence
Curr Biol
Regulation of opioid receptor trafficking and morphine tolerance by receptor oligomerization
Cell
Repeated electroconvulsive shock or chronic morphine treatment increase the number of 3H-D-Ala2, D-Leu5-enkephalin binding sites in rat brain membranes
Life Sci
Comparison of in vivo and in vitro parameters of opioid receptor binding in naive and tolerant/dependent rodents
Life Sci
Morphine activates opioid receptors without causing their rapid internalization
J Biol Chem
Carboxyl-terminal splicing of the rat μ-opioid receptor modulates agonist-mediated internalization and receptor resensitization
J Biol Chem
C-terminal splice variants of the mouse μ-opioid receptor differ in morphine-induced internalization and receptor resensitization
J Biol Chem
ADP-ribosylation factor-dependent Phospholipase D2 activation is required for agonist-induced μ-opioid receptor endocytosis
J Biol Chem
Endocytosis and recycling of G protein-coupled receptors
Trends Pharmacol Sci
Agonist-induced desensitization of the μ opioid receptor-coupled potassium channel (GIRK1)
J Biol Chem
Down-regulation of opiate receptor in neuroblastoma × glioma NG108-15 hybrid cells. Chloroquine promotes accumulation of tritiated enkephaline in the lysosomes
J Biol Chem
Constitutively active mu-opioid receptors inhibit adenylyl cyclase activity in intact cells and activate G-proteins differently than the agonist [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin
J Biol Chem
Ligand-induced μ-opioid receptor endocytosis and recycling in enteric neurons
Neuroscience
Inhibition of protein kinase C, but not of protein kinase A, blocks the development of acute antinociceptive tolerance to an intrathecally administered μ-opioid receptor agonist in the mouse
Eur J Pharmacol
A mitogen-activated protein kinase pathway is required for μ-opioid receptor desensitization
J Biol Chem
Chronic morphine induced tolerance and desensitization of mu-opioid receptor but not downregulation in rabbit
Eur J Pharmacol
Morphine-induced desensitization and down-regulation at mu-receptor in 7315 C pituitary tumor cells
Life Sci
μ-Opioid receptor desensitization: role of receptor phosphorylation, internalization, and resensitization
J Biol Chem
A novel endocytic recycling signal that distingishes the membrane trafficking of naturally occurring opioid receptors
J Biol Chem
[D-ALAla2,N-MEPHE4, GLY-OL5]encephalin-induced internalization of the μ-opioid receptor in the spinal cord of morphine tolerant rats
Neuroscience
Opioid-induced adenylyl cyclase supersensitization in human embryonic kidney 293 cells requires pertussis toxin-sensitive G proteins othet than G(i1) and G(i3)
Neurosci Lett
Internalization of μ-opioid receptor produced by etorphine in the rat locus coeruleus
Neuroscience
Functional coupling, desensitization and internalization of virally expressed mu opioid receptors in cultured dorsal root ganglion neurons from mu opioid receptor knockout mice
Neuroscience
μ-Opioid receptor–effector coupling and trafficking in dorsal root ganglia neurons
Neuroscience
Tolerance to morphine at the μ-opioid receptor differentially induced by cAMP-dependent protein kinase activation and morphine
Eur J Pharmacol
μ-Opioid receptors: ligand-dependent activation of potassium conductance, desensitization, and internalization
J Neurosci
Phosphorylation and agonist-specific intracellular trafficking of an epitope-tagged μ-opioid receptor expressed in HEK 293 cells
J Neurochem
μ-opioid receptor desensitization in mature rat neurons: lack of interaction between DAMGO and morphine
J Neurosci
Protein kinase C activation enhances morphine-induced rapid desensitization of μ-opioid receptors in mature rat locus ceruleus neurons
Mol Pharmacol
μ-Opioid receptor desensitization by β-arrestin-2 determines morphine tolerance but not dependence
Nature
Distinct domains of the μ-opioid receptor control uncoupling and internalization
Mol Pharmacol
The μ-opioid receptor down-regulates differently from the delta-opioid receptor: requirement of a high affinity receptor/G protein complex formation
Mol Pharmacol
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