Cellular Morphine Tolerance Produced by βArrestin-2-Dependent Impairment of μ-Opioid Receptor Resensitization

Dang, Vu C.; Chieng, Billy; Azriel, Yael; Christie, MacDonald J.

doi:10.1523/jneurosci.5999-10.2011

Cited by 61 publications

(106 citation statements)

References 42 publications

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“…The precise role of arrestins in MOPr regulation in neurons remains to be fully elucidated. Although MOPr desensitization by high-efficacy agonists such as DAMGO is arrestin-dependent in cell lines (Chu et al, 2008), the acute desensitization induced by Met-enkephalin was unaffected in LC neurons from arrestin-3-knockout mice (Dang et al, 2011;Quillinan et al, 2011). These studies suggest that arrestins play a complex role in MOPr function in neurons, with recovery from acute desensitization being much faster in neurons from arrestin-3-knockout mice (Dang et al, 2011;Quillinan et al, 2011).…”

Section: Discussionmentioning

confidence: 82%

“…Although MOPr desensitization by high-efficacy agonists such as DAMGO is arrestin-dependent in cell lines (Chu et al, 2008), the acute desensitization induced by Met-enkephalin was unaffected in LC neurons from arrestin-3-knockout mice (Dang et al, 2011;Quillinan et al, 2011). These studies suggest that arrestins play a complex role in MOPr function in neurons, with recovery from acute desensitization being much faster in neurons from arrestin-3-knockout mice (Dang et al, 2011;Quillinan et al, 2011). Given that MOPr dephosphorylation can occur at the cell surface (Arttamangkul et al, 2006;Doll et al, 2011), arrestin interaction and internalization might actually reduce the rate of MOPr resensitization, which might be manifested as an enhanced rate of desensitization, as observed in our LC neuron study.…”

Section: Discussionmentioning

confidence: 93%

See 1 more Smart Citation

Endomorphin-2: A Biased Agonist at the μ-Opioid Receptor

Rivero¹,

Llorente²,

McPherson³

et al. 2012

Mol Pharmacol

101

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Previously we correlated the efficacy for G protein activation with that for arrestin recruitment for a number of agonists at the -opioid receptor (MOPr) stably expressed in HEK293 cells. We suggested that the endomorphins (endomorphin-1 and -2) might be biased toward arrestin recruitment. In the present study, we investigated this phenomenon in more detail for endomorphin-2, using endogenous MOPr in rat brain as well as MOPr stably expressed in HEK293 cells. For MOPr in neurons in brainstem locus ceruleus slices, the peptide agonists [DAla 2 ,N-Me-Phe 4 ,Gly 5 -ol]-enkephalin (DAMGO) and endomorphin-2 activated inwardly rectifying K ϩ current in a concentrationdependent manner. Analysis of these responses with the operational model of pharmacological agonism confirmed that endomorphin-2 had a much lower operational efficacy for G protein-mediated responses than did DAMGO at native MOPr in mature neurons. However, endomorphin-2 induced faster desensitization of the K ϩ current than did DAMGO. In addition, in HEK293 cells stably expressing MOPr, the ability of endomorphin-2 to induce phosphorylation of Ser375 in the COOH terminus of the receptor, to induce association of arrestin with the receptor, and to induce cell surface loss of receptors was much more efficient than would be predicted from its efficacy for G protein-mediated signaling. Together, these results indicate that endomorphin-2 is an arrestin-biased agonist at MOPr and the reason for this is likely to be the ability of endomorphin-2 to induce greater phosphorylation of MOPr than would be expected from its ability to activate MOPr and to induce activation of G proteins.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 93%

Endomorphin-2: A Biased Agonist at the μ-Opioid Receptor

Rivero¹,

Llorente²,

McPherson³

et al. 2012

Mol Pharmacol

101

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show abstract

“…Such constitutive activity also explains the reduced VDCC inhibition by mu agonists in b-arr2À/À neurons (Table 1; Figure 5; Lam et al, 2011;Walwyn et al, 2007). The well-known attenuated morphine desensitization and tolerance of the mu receptor in b-arr2À/À mice may result from b-arrestin 2 inhibition of mu receptor resensitization, independent of receptor internalization (Dang et al, 2011;Quillinan et al, 2011). This could explain the lack of desensitization of DAMGO-VDCC inhibition following chronic morphine treatments in b-arr2À/À neurons seen in Figure 5.…”

Section: Discussionmentioning

confidence: 82%

“…As morphine does not induce significant internalization of the mu opioid receptor, the effects of morphine in b-arr2À/À mice cannot be explained by this prototypical role of barrestin 2. However, some progress has recently been made in revealing several arrestin-dependent, yet internalizationindependent, signaling pathways of the mu opioid receptor that explain some, but not all, effects of morphine in mice lacking b-arrestin 2 (Arttamangkul et al, 2008;Dang et al, 2011;Quillinan et al, 2011;Walwyn et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Evidence that Behavioral Phenotypes of Morphine in β-arr2−/− Mice Are Due to the Unmasking of JNK Signaling

Mittal

Tan

Egbuta

et al. 2012

Neuropsychopharmacol

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The altered behavioral effects of morphine, but not most other mu agonists, in mice lacking b-arrestin 2, suggest that this scaffolding protein regulates the signaling cascade of this commonly used analgesic. One of the cascades that could be regulated by b-arrestin 2 is cJun-N-terminal kinase (JNK), which binds with b-arrestin 2 and modulates the analgesic effects of morphine. Using neurons lacking b-arrestin 2 (b-arr2À/À) to examine this interaction, we found that b-arr2À/À neurons show altered intracellular distribution of JNK and cJun, and that morphine, but not fentanyl, increased the nuclear localization of the phosphorylated, therefore activated, form of cJun, a JNK target in dorsal root ganglia neurons. This suggests that deleting b-arrestin 2 affects the JNK cascade. We therefore examined whether some of the behavioral phenotypes of mice lacking b-arrestin 2 could be a result of altered JNK signaling. Indeed, two different JNK inhibitors reversed the enhanced analgesic effect of morphine, a known phenotype of b-arr2À/À mice, to + / + levels. Both the reduced locomotor effect of morphine and the psychomotor sensitization to repeated morphine administration in b-arr2À/À mice were also returned to + / + levels by inhibiting JNK. In contrast, the behavioral effects of fentanyl were neither genotype-dependent nor affected by JNK inhibition. Furthermore, a PKC inhibitor had a similar effect as inhibiting JNK in reducing the enhanced analgesic effect of morphine in b-arr2À/À mice to + / + levels. In summary, removing b-arrestin 2 reveals mu receptor activation of the JNK cascade in a ligand-specific manner explaining several behavioral phenotypes of b-arr2À/À mice.

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“…Similar, intracerebroventricular injection of a smallmolecule GRK2 inhibitor reversed tolerance to DAMGO but not to morphine (Hull et al, 2010). Conversely, mice lacking ␤-arrestin-2 show diminished antinociceptive tolerance to morphine only but not to high-efficacy agonists such as fentanyl or methadone (Bohn et al, 1999(Bohn et al, , 2000Dang et al, 2011;Raehal and Bohn, 2011). Moreover, inhibition of PKC reversed tolerance to morphine but not to DAMGO (Bailey et al, 2006(Bailey et al, , 2009Hull et al, 2010).…”

Section: Discussionmentioning

confidence: 91%

Analgesic Tolerance to High-Efficacy Agonists But Not to Morphine Is Diminished in Phosphorylation-Deficient S375A μ-Opioid Receptor Knock-In Mice

Grecksch¹,

Just²,

Pierstorff³

et al. 2011

J. Neurosci.

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Morphine is one of the most potent analgesic drugs. However, the utility of morphine in the management of chronic pain is limited by its rapid development of tolerance. Morphine exerts all of its pharmacological effects via the -opioid receptor. In many systems, tolerance is associated with phosphorylation and desensitization of G-protein-coupled receptors (GPCRs). In case of the -opioid receptor, phosphorylation occurs in an agonist-selective manner. High-efficacy agonists such as [D-Ala 2 -MePhe 4 -Gly-ol]enkephalin (DAMGO), fentanyl, or etonitazene stimulate the phosphorylation of both C-terminal threonine 370 (T370) and serine 375 (S375). In contrast, morphine promotes the phosphorylation of S375 but fails to stimulate T370 phosphorylation. Here, we have assessed the contribution of S375 phosphorylation to the development of antinociceptive tolerance to high-and low-efficacy agonists in vivo. We show that S375 phosphorylation of the -opioid receptor occurs in intact mouse brain in a dose-dependent manner after administration of morphine, fentanyl, or etonitazene. In knock-in mice expressing the phosphorylation-deficient S375A mutant of the -opioid receptor, morphine and fentanyl exhibited greater dose-dependent antinociceptive responses than in wild-type mice. However, acute and chronic tolerance to morphine was retained in S375A mutant mice. In contrast, antinociceptive tolerance after repeated subcutaneous application of etonitazene or repeated intracerebroventricular application of DAMGO was diminished. Thus, tolerance to agonists with different efficacies develops through distinct pathways. Whereas tolerance induced by DAMGO or etonitazene requires agonist-driven phosphorylation of S375, the development and maintenance of antinociceptive tolerance to morphine occurs independent of S375 phosphorylation.

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Cellular Morphine Tolerance Produced by βArrestin-2-Dependent Impairment of μ-Opioid Receptor Resensitization

Cited by 61 publications

References 42 publications

Endomorphin-2: A Biased Agonist at the μ-Opioid Receptor

Endomorphin-2: A Biased Agonist at the μ-Opioid Receptor

Evidence that Behavioral Phenotypes of Morphine in β-arr2−/− Mice Are Due to the Unmasking of JNK Signaling

Analgesic Tolerance to High-Efficacy Agonists But Not to Morphine Is Diminished in Phosphorylation-Deficient S375A μ-Opioid Receptor Knock-In Mice

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