Modulating μ-Opioid Receptor Phosphorylation Switches Agonist-dependent Signaling as Reflected in PKCϵ Activation and Dendritic Spine Stability

Zheng, Hui; Chu, Ji; Zhang, Yuhan; Loh, Horace H.; Law, Ping Yee

doi:10.1074/jbc.m110.177089

Cited by 40 publications

(64 citation statements)

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“…When compared with other mu agonists, morphine induces less internalization of the mu opioid receptor (Borgland et al, 2003;McPherson et al, 2010;Zheng et al, 2011). This suggests that the prototypical role of b-arrestin 2 in initiating receptor internalization does not explain how the effects of morphine, but not of other mu agonists, are altered in mice lacking b-arrestin 2.…”

Section: Discussionmentioning

confidence: 64%

“…Compared with other mu agonists such as fentanyl, the relative inability of morphine to cause significant receptor phosphorylation, results in the recruitment of PKC to morphine, but not fentanyl, bound mu receptors (Zheng et al, 2011). As PKC is known to both scaffold with and phosphorylate JNK (Lopez-Bergami et al, 2005;Ping, 2003;Pontrelli et al, 2004), we propose that in wild-type mice, morphine recruitment of PKC activates JNK but that barrestin 2 recruitment limits further JNK activation.…”

Section: Discussionmentioning

confidence: 95%

“…However, if b-arrestin 2 is absent and is coupled with the inability of morphine to recruit b-arrestin 1 (Groer et al, 2011), sufficient PKC recruitment results in sustained activation of the JNK cascade in b-arr2À/À neurons to affect analgesia. In contrast, other mu agonists, such as fentanyl differ from morphine as they are able to phosphorylate the mu receptor and recruit either b-arrestin 1 or 2 (Groer et al, 2011;Zheng et al, 2011). In the absence of b-arrestin 2, these agonists recruit b-arrestin 1, PKC is not recruited and the JNK cascade is not significantly activated.…”

Section: Discussionmentioning

confidence: 97%

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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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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 97%

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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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“…Differential phosphorylation, tissue-, cell-, or agonist-dependent, has recently been postulated to create a "phosphorylation bar code" that offers a way to regulate signaling and trafficking of GPCRs (52). Such a mechanism could explain, for example, the differences in MOP receptor desensitization and trafficking induced by morphine versus DAMGO (5,38,49,50,54) or could determine the signaling pathway (PKC⑀ versus ␤-arrestin2) by which MOP agonists activate ERK (55). Cross-or transphosphorylation between receptors offers an additional level of complexity to the regulation of GPCR activity and trafficking (56) that could be involved in the functional inhibition of MOP receptors by NPFF receptors.…”

Section: Discussionmentioning

confidence: 99%

GRK2 Protein-mediated Transphosphorylation Contributes to Loss of Function of μ-Opioid Receptors Induced by Neuropeptide FF (NPFF2) Receptors

Moulédous

Froment

Dauvillier

et al. 2012

Journal of Biological Chemistry

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Background: Neuropeptide FF 2 receptors interact with -opioid receptors and decrease their activity. Results: The phosphorylation pattern of MOP receptor is similar after homologous (DAMGO) and heterologous (neuropeptide FF) stimulation. Conclusion: GPCR kinase 2 (GRK2) contributes to the NPFF-induced phosphorylation and loss of function of MOP receptor. Significance: GRK2-mediated transphosphorylation within receptor heteromers could play a role in heterologous desensitization of GPCRs.

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“…The present study showed that the change in the MOR binding affinity is not likely to be the mechanism for the fentanyldependent attenuation of MOR activation in oxaliplatininduced neuropathy. The second possibility for decreased G protein activation by fentanyl is upregulation of G protein-coupled receptor kinases (GRKs) because upregulation of the expression of GRKs might reduce opioid-stimulated G protein activation in animal pain models (34), and fentanyl showed a stronger interaction with the arrestin-GRK pathway compared with morphine (35,36). Therefore, we examined the expression level of GRK2, a major link to MOR, in the mTH in the oxaliplatin group by western blotting.…”

Section: Discussionmentioning

confidence: 99%

The Contribution of Gi/o Protein to Opioid Antinociception in an Oxaliplatin-Induced Neuropathy Rat Model

Kanbara¹,

Nakamura²,

Takasu³

et al. 2014

J Pharmacol Sci

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Abstract.Oxaliplatin is a chemotherapeutic agent that induces chronic refractory neuropathy. To determine whether opioids effectively relieve this chronic neuropathy, we investigated the efficacies of morphine, oxycodone, and fentanyl, and the mechanisms underlying opioid antinociception, in oxaliplatin-induced neuropathy in rats. Rats exhibited significant mechanical allodynia following 2 weeks of chronic oxaliplatin administration. Within the range of doses that did not induce sedation and/or muscle rigidity, morphine (3 mg/kg, subcutaneously, s.c.) and oxycodone (0.3 -0.56 mg/kg, s.c.) completely reversed oxaliplatin-induced mechanical allodynia, whereas fentanyl (0.017 -0.03 mg/kg, s.c.) showed partial antinociception. The antinociception of the optimal doses of morphine and oxycodone were completely inhibited by pertussis toxin (PTX; 0.5 mg/rat, i.c.v.), a Gi/o protein inhibitor, while the partial effect of fentanyl was not affected in the oxaliplatin model. In the [35 S]-GTPgS binding assay, activation of m-opioid receptor by fentanyl, but not by morphine or oxycodone, in the mediodorsal thalamus was significantly reduced in oxaliplatin-treated rats. These results indicate that the lower antinociceptive potency of fentanyl in the oxaliplatin model might in part result from the loss of PTX-sensitive Gi/o protein activation, and the degree of Gi/o protein activation might be related to the potency of antinociception by opioids in this model.

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Modulating μ-Opioid Receptor Phosphorylation Switches Agonist-dependent Signaling as Reflected in PKCϵ Activation and Dendritic Spine Stability

Cited by 40 publications

References 41 publications

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

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

GRK2 Protein-mediated Transphosphorylation Contributes to Loss of Function of μ-Opioid Receptors Induced by Neuropeptide FF (NPFF2) Receptors

The Contribution of Gi/o Protein to Opioid Antinociception in an Oxaliplatin-Induced Neuropathy Rat Model

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