Chronic Morphine Treatment Reduces Recovery from Opioid Desensitization

Dang, Vu C.; Williams, John T.

doi:10.1523/jneurosci.2499-04.2004

Cited by 64 publications

(89 citation statements)

References 33 publications

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“…Receptor resensitization was assessed by comparing MOR activation of GIRK by ME (300 nM) before and at various times after desensitization. Consistent with previous reports (Osborne and Williams, 1995;Dang and Williams, 2004), MOR activation of GIRK exhibited slow but progressive recovery after the washout of ME (30 M; 10 min). In neurons from w.t.…”

Section: Resultssupporting

confidence: 92%

“…mice is depressed and shifted to the right, representing MOR tolerance in single neurons (two-factor ANOVA, drug treatment effect, p Ͻ 0.0001). This is consistent with previous reports for LC neurons from morphine-treated rats (Christie et al, 1987;Dang and Williams, 2004). When the same experiments were conducted in neurons from morphine-treated ␤arr-2 k.o.…”

Section: Inhibition Of Protein Phosphatase Function Prevents Mor Resesupporting

confidence: 93%

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

Dang

Chieng²,

Azriel³

et al. 2011

J. Neurosci.

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Chronic morphine treatment produces behavioral and cellular opioid tolerance that has been proposed to be caused by attenuated -opioid receptor (MOR) recovery from desensitization (resensitization). The process of MOR resensitization is thought to require ␤arrestin-2 (␤arr-2)-dependent trafficking of desensitized receptors to endosomal compartments, followed by recycling of resensitized receptors back to the plasma membrane. However, there is little direct evidence for this, particularly in native neurons. This study used whole-cell patch-clamp recording in locus ceruleus (LC) neurons from wild-type (w.t.) and ␤arr-2 knock-out (k.o.) mice to examine whether ␤arr-2/dynamin-dependent trafficking is required for MOR resensitization in neurons from opioid-naive and morphine-treated mice. Surprisingly, recovery of MOR from acute desensitization in LC neurons does not require ␤arr-2-or dynamin-dependent trafficking. To the contrary, MOR resensitization was accelerated by disruption of either ␤arr-2 or dynamin function. Chronic morphine treatment caused cellular MOR tolerance and concurrently impaired MOR resensitization in neurons from w.t. mice, as expected from previous studies, but neither occurred in neurons from ␤arr-2 k.o. mice. Moreover, the impairment of MOR resensitization caused by chronic morphine was reversed in w.t. neurons when G-protein-coupled receptor kinase-2 (GRK2) or dynamin function was disrupted. Together, these results establish that ␤arr-2/dynamin-dependent receptor regulation is not required for MOR resensitization in LC neurons. Furthermore, chronic morphine treatment modifies GRK2-␤arr-2-dynamin-dependent MOR trafficking to impair receptor resensitization, thereby contributing to opioid tolerance in LC neurons by reducing the number of functional receptors on the surface membrane.

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Section: Resultssupporting

confidence: 92%

Section: Inhibition Of Protein Phosphatase Function Prevents Mor Resesupporting

confidence: 93%

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

Dang

Chieng²,

Azriel³

et al. 2011

J. Neurosci.

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“…Therefore, it is likely that m-opioid receptor coupling to GIRK channels is fully desensitized due to the presence of agonist during the recordings. Consistent with this idea is the observation that recovery from desensitization is slow after chronic morphine treatment (Dang and Williams, 2004). The present data are also consistent with previous studies showing profound GIRK desensitization with chronic morphine pretreatment (Christie et al, 1987;Chieng and Christie, 1996;Bagley et al, 2005a, b).…”

Section: Discussionsupporting

confidence: 93%

Tolerance to Repeated Morphine Administration Is Associated with Increased Potency of Opioid Agonists

Ingram

Macey

Fossum

et al. 2007

Neuropsychopharmacol

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Tolerance to the pain-relieving effects of opiates limits their clinical use. Although morphine tolerance is associated with desensitization of m-opioid receptors, the underlying cellular mechanisms are not understood. One problem with the desensitization hypothesis is that acute morphine does not readily desensitize m-opioid receptors in many cell types. Given that neurons in the periaqueductal gray (PAG) contribute to morphine antinociception and tolerance, an understanding of desensitization in PAG neurons is particularly relevant. Opioid activity in the PAG can be monitored with activation of G-protein-mediated inwardly rectifying potassium (GIRK) currents. The present data show that opioids have a biphasic effect on GIRK currents in morphine tolerant rats. Opioid activation of GIRK currents is initially potentiated in morphine (EC 50 ¼ 281 nM) compared to saline (EC 50 ¼ 8.8 mM) pretreated rats as indicated by a leftward shift in the concentration-response curve for met-enkephalin (ME)-induced currents. These currents were inhibited by superfusion of the m-opioid receptor antagonist b-funaltrexamine (b-FNA) suggesting that repeated morphine administration enhances agonist stimulation of m-opioid receptor coupling to G-proteins. Although supersensitivity of m-opioid receptors in the PAG is counterintuitive to the development of tolerance, peak GIRK currents from tolerant rats desensitized more than currents from saline pretreated rats (56% of peak current after 10 min compared to 15%, respectively). These data indicate that antinociceptive tolerance may be triggered by enhanced agonist potency resulting in increased desensitization of m-opioid receptors.

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“…(Walwyn et al, 2007) reinforces suggests multiple mechanisms mediate desensitization in neurons other than LC [but see Li and Wang (2001)]. Differential adaptations to ERK1/2-and GRK2-␤arr-2-function might also be responsible for the enhanced desensitization and the failure of MOR to recover from desensitization that result in reduced MOR signaling after chronic morphine treatment (Dang and Williams, 2004). Understanding these specific adaptations may facilitate the development of drugs that can reduce tolerance.…”

Section: Discussionmentioning

confidence: 95%

Two Distinct Mechanisms Mediate Acute μ-Opioid Receptor Desensitization in Native Neurons

Dang

Napier²,

Christie³

2009

J. Neurosci.

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Sustained stimulation of G-protein coupled receptors (GPCRs) leads to rapid loss of receptor function (acute desensitization). For manyGPCRs including the -opioid receptor (MOR), an accepted mechanism for acute desensitization is through G-protein coupled receptor kinase (GRKs) mediated phosphorylation of the receptor, which facilitates the binding of ␤-arrestins (␤arrs) to the receptor and then promotes endocytosis. However, the mechanism(s) that mediate acute desensitization have not yet been well defined in native neurons. This study used whole-cell patch clamp recording of G-protein coupled inward-rectifying potassium (GIRK) currents to assay MOR function and identify mechanisms of acute MOR desensitization in locus ceruleus (LC) neurons. The rate and extent of MOR desensitization were unaffected by ␤arr-2 knock-out. Disruption of GRK2 function via inhibitory peptide introduced directly into neurons also failed to affect desensitization in wild type or ␤arr-2 knock-outs. Inhibition of ERK1/2 activation alone had little effect on acute desensitization. However, when both GRK2-␤arr-2 and ERK1/2 functions were disrupted simultaneously, desensitization of MOR was nearly abolished. Together, these results suggest that acute desensitization of MOR in native LC neurons is determined by at least two molecular pathways, one involving GRK2 and ␤arr-2, and a parallel pathway mediated by activated ERK1/2.

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Chronic Morphine Treatment Reduces Recovery from Opioid Desensitization

Cited by 64 publications

References 33 publications

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

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

Tolerance to Repeated Morphine Administration Is Associated with Increased Potency of Opioid Agonists

Two Distinct Mechanisms Mediate Acute μ-Opioid Receptor Desensitization in Native Neurons

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