Functional Selectivity at the μ-Opioid Receptor: Implications for Understanding Opioid Analgesia and Tolerance

Raehal, Kirsten M.; Schmid, Cullen L.; Groer, Chad E.; Bohn, Laura M.

doi:10.1124/pr.111.004598

Cited by 229 publications

(239 citation statements)

References 155 publications

(252 reference statements)

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“…Although morphine does not induce tolerance in the hot plate test following chronic pump administration in ␤arr2-KO mice (48 mg/kg/day EC 50 shift, ϳ1.3-fold over basal) compared with WT mice (same dose, EC 50 shift ϳ3-fold), methadone and fentanyl produce equivalent degrees of tolerance in both genotypes (ϳ2-fold shift in EC 50 ). Interestingly, in contrast to morphine, these latter two agonists lead to MOR phosphorylation to the same extent as etorphine or DAMGO (3,54). It is attractive to speculate that in the absence of ␤-arrestin2, ␤-arrestin1 can substitute for agonists that promote robust phosphorylation of the MOR, such as fentanyl and methadone, to lead to desensitization and antinociceptive tolerance (19,21).…”

Section: Discussionmentioning

confidence: 99%

Agonist-directed Interactions with Specific β-Arrestins Determine μ-Opioid Receptor Trafficking, Ubiquitination, and Dephosphorylation

Groer

Schmid

Jaeger

et al. 2011

Journal of Biological Chemistry

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115

112

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Morphine and other opiates mediate their effects through activation of the -opioid receptor (MOR), and regulation of the MOR has been shown to critically affect receptor responsiveness. Activation of the MOR results in receptor phosphorylation, ␤-arrestin recruitment, and internalization. This classical regulatory process can differ, depending on the ligand occupying the receptor. There are two forms of ␤-arrestin, ␤-arrestin1 and ␤-arrestin2 (also known as arrestin2 and arrestin3, respectively); however, most studies have focused on the consequences of recruiting ␤-arrestin2 specifically. In this study, we examine the different contributions of ␤-arrestin1-and ␤-arrestin2-mediated regulation of the MOR by comparing MOR agonists in cells that lack expression of individual or both ␤-arrestins. Here we show that morphine only recruits ␤-arrestin2, whereas the MOR-selective enkephalin [D-Ala 2 ,N-MePhe 4 ,Gly 5 -ol]enkephalin (DAMGO), recruits either ␤-arrestin. We show that ␤-arrestins are required for receptor internalization and that only ␤-arrestin2 can rescue morphine-induced MOR internalization, whereas either ␤-arrestin can rescue DAMGO-induced MOR internalization. DAMGO activation of the receptor promotes MOR ubiquitination over time. Interestingly, ␤-arrestin1 proves to be critical for MOR ubiquitination as modification does not occur in the absence of ␤-arrestin1 nor when morphine occupies the receptor. Moreover, the selective interactions between the MOR and ␤-arrestin1 facilitate receptor dephosphorylation, which may play a role in the resensitization of the MOR and thereby contribute to overall development of opioid tolerance.Morphine and other opiates are among the most clinically useful analgesics, and their actions are mediated largely through activation of -opioid receptors (MORs).3 As a G protein-coupled receptor (GPCR), the MOR is subject to regulation paradigms that include phosphorylation by GPCR kinases (GRKs) and subsequent interactions with ␤-arrestins (␤-arrestin1, also known as arrestin2, and ␤-arrestin2, also known as arrestin3). ␤-Arrestins can then initiate receptor internalization, which in turn can promote both receptor down-regulation and resensitization (1-3). ␤-Arrestins can also facilitate these regulatory events by scaffolding ubiquitination machinery, such as E3 ligases, to GPCRs, as has been shown for the ␤ 2 adrenergic receptor (␤ 2 AR), V2 vasopressin receptor, and the chemokine receptor (CXCR4) (4 -6), however this has not been demonstrated for the MOR. MOR regulation has been shown to be contingent upon the particular agonist acting at the receptor as morphine promotes different regulatory events than other opioid ligands, including the D-enkephalin analog, [D-Ala 2 ,N-Me-Phe 4 ,Gly 5 -ol]enkephalin (DAMGO), fentanyl, methadone, and etorphine, although all of these ligands are full agonists at the MOR with respect to G protein coupling (7). The difference between agonists was first recognized when Arden et al. (8) observed that although DAMGO promotes robust internalizatio...

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Section: Discussionmentioning

confidence: 99%

Agonist-directed Interactions with Specific β-Arrestins Determine μ-Opioid Receptor Trafficking, Ubiquitination, and Dephosphorylation

Groer

Schmid

Jaeger

et al. 2011

Journal of Biological Chemistry

Self Cite

115

112

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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%

“…Accordingly, MOP receptor heterologously phosphorylated by activation of NPFF 2 receptor can recruit ␤-arrestin2, but because its phosphorylation level is too low, and probably also because it does not adopt a proper agonist-active conformation, the receptor-␤-arrestin complex could either be not stable enough or in an inappropriate conformation to recruit the endocytic machinery. However, ␤-arrestin2 can also play a role in desensitization independently from internalization (5,71) and could therefore contribute to NPFF 2 -induced MOP receptor loss of function by disrupting G i protein activation or by means of its scaffolding properties.…”

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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“…Mu agonist-induced receptor phosphorylation and subsequent β-arrestin binding have been postulated as one mechanism of receptor desensitization and mu opioid tolerance (42)(43)(44). For example, serine 375 (S375) of MOR-1 in exon 3-encoded C-terminal sequences shared by all C-terminal variants can be phosphorylated mainly by GRK5 (62), contributing to β-arrestin recruitment (63).…”

Section: Discussionmentioning

confidence: 99%

Alternatively spliced mu opioid receptor C termini impact the diverse actions of morphine

Xu¹,

Lu²,

Narayan³

et al. 2017

Journal of Clinical Investigation

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Functional Selectivity at the μ-Opioid Receptor: Implications for Understanding Opioid Analgesia and Tolerance

Cited by 229 publications

References 155 publications

Agonist-directed Interactions with Specific β-Arrestins Determine μ-Opioid Receptor Trafficking, Ubiquitination, and Dephosphorylation

Agonist-directed Interactions with Specific β-Arrestins Determine μ-Opioid Receptor Trafficking, Ubiquitination, and Dephosphorylation

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

Alternatively spliced mu opioid receptor C termini impact the diverse actions of morphine

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