μ-Opioid receptor downregulation contributes to opioid tolerance in vivo

Stafford, Kristi; Gomes, A.Benedict; Shen, Jing; Yoburn, Byron C.

doi:10.1016/s0091-3057(01)00525-1

Cited by 80 publications

(68 citation statements)

References 22 publications

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“…Our studies showing that DAMGO, but not morphine, induces ubiquitination of the MOR could indicate that the DAMGO-bound receptor is then degraded, whereas the morphine-bound receptor is not. This would be in agreement with several studies that have observed that chronic treatment with morphine does not cause MOR down-regulation in whole mouse brain or brainstem (19,(51)(52)(53), which may be due to morphine's inability to promote MOR ubiquitination.…”

Section: Discussionsupporting

confidence: 93%

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

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: Discussionsupporting

confidence: 93%

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

115

112

View full text Add to dashboard Cite

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“…The effects of chronic morphine administration on MOP binding site density have also been investigated in animal brain and brain regions. These studies produced all possible changes in MOP density, namely, up-regulation (Besse et al, 1992;Brady et al, 1989;Fabian et al, 2002;Fabian et al, 2003;Holaday et al, 1982;Ray et al, 2004;Rothman et al, 1991;Schmidt et al, 2003;Vigano et al, 2003), down-regulation (Bhargava and Gulati, 1990;Meuser et al, 2003;Werling et al, 1989) or no change (Polastron et al, 1994;Stafford et al, 2001;Turchan et al, 1999). Some of these results appear to be regional differences, but others, performed on whole brain or the same regions of the same animal, appear to be discrepancies between different laboratories.…”

Section: Discussionmentioning

confidence: 99%

Chronic morphine treatment up-regulates mu opioid receptor binding in cells lacking filamin A

Onoprishvili

Simon

2007

Brain Research

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We investigated the effects of morphine and other agonists on the human mu opioid receptor (MOP) expressed in M2 melanoma cells, lacking the actin cytoskeleton protein filamin A and in A7, a sub clone of the M2 melanoma cells, stably transfected with filamin A cDNA. The results of binding experiments showed, that after chronic morphine treatment (24 hr) of A7 cells, MOP binding sites were down-regulated to 63% of control, whereas, unexpectedly, in M2 cells, MOP binding was upregulated to 188% of control naïve cells. Similar up-regulation was observed with the agonists methadone and levorphanol. The presence of antagonists (naloxone or CTAP) during chronic morphine treatment inhibited MOP down-regulation in A7 cells. In contrast, morphine-induced upregulation of MOP in M2 cells was further increased by these antagonists. Chronic morphine desensitized MOP in A7 cells, i.e. it decreased DAMGO-induced stimulation of GTPγS binding. In M2 cells DAMGO stimulation of GTPγS binding was significantly greater than in A7 cells and was not desensitized by chronic morphine. Pertussis toxin treatment abolished morphine-induced receptor up-regulation in M2 cells, whereas it had no effect on morphine-induced down-regulation in A7 cells. These results indicate that, in the absence of filamin A, chronic treatment with morphine, methadone or levorphanol leads to up-regulation of MOP, to our knowledge, the first instance of opioid receptor up-regulation by agonists in cell culture.

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“…An alternative explanation for the reduction in morphine tolerance observed in β-arrestin KO mice is that, although it is not an internalizing opioid, morphine binds to MORs that exist as heterodimers, with the second OR subtype interacting with β-arrestin and the subsequent internalization of the morphine-heterodimer complex contributes to tolerance (46,47). However, the validity of this hypothesis appears unlikely, as the results were not reproducible in later experiments and depended on the co-administration of morphine with an internalizing opioid for dimer endocytosis, and chronic morphine exposure does not change MOR expression (46,48,49).…”

Section: Mu-opioid Receptor-mediated Changesmentioning

confidence: 99%

Opioid Tolerance Development: A Pharmacokinetic/Pharmacodynamic Perspective

Dumas

Pollack

2008

AAPS J

231

164

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Abstract. The opioids are commonly used to treat acute and severe pain. Long-term opioid administration eventually reaches a dose ceiling that is attributable to the rapid onset of analgesic tolerance coupled with the slow development of tolerance to the untoward side effects of respiratory depression, nausea and decreased gastrointestinal motility. The need for effective-long term analgesia remains. In order to develop new therapeutics and novel strategies for use of current analgesics, the processes that mediate tolerance must be understood. This review highlights potential pharmacokinetic (changes in metabolite production, metabolizing enzyme expression, and transporter function) and pharmacodynamic (receptor type, location and functionality; alterations in signaling pathways and crosstolerance) aspects of opioid tolerance development, and presents several pharmacodynamic modeling strategies that have been used to characterize time-dependent attenuation of opioid analgesia.

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μ-Opioid receptor downregulation contributes to opioid tolerance in vivo

Cited by 80 publications

References 22 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

Chronic morphine treatment up-regulates mu opioid receptor binding in cells lacking filamin A

Opioid Tolerance Development: A Pharmacokinetic/Pharmacodynamic Perspective

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