Differential Activation and Trafficking of μ-Opioid Receptors in Brain Slices

Arttamangkul, Seksiri; Quillinan, Nidia; Low, Malcolm J.; Zastrow, Mark von; Pintar, John E.; Williams, John T.

doi:10.1124/mol.108.048512

Cited by 99 publications

(144 citation statements)

References 36 publications

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“…This reconciles and extends previous reports that deletion of ␤arr-2 does not prevent acute MOR desensitization (Dang and Christie, 2006;Walwyn et al, 2007;Arttamangkul et al, 2008). Indeed, when MOR function was probed with a low concentration of agonist (ME; 300 nM) to avoid any potential influence of spare receptors (Connor et al, 2004), the rate and extent of desensitization were unaffected by ␤arr-2 deletion.…”

Section: Discussionsupporting

confidence: 72%

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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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Section: Discussionsupporting

confidence: 72%

“…2). As previously reported in LC from rat and mouse (Arttamangkul et al, 2006(Arttamangkul et al, , 2008, brief treatment with supramaximal ( Fig. 1) concentrations of ME (10 -30 M; Յ2 min) reduced the current activated by a submaximal (Fig.…”

Section: ␤-Arrestin-2 Deletion Does Not Affect Acute Desensitization supporting

confidence: 49%

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

Dang

Napier²,

Christie³

2009

J. Neurosci.

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“…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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“…Furthermore, when the cells were allowed to recover for 2 min, the morphinemediated Ca 2ϩ current inhibition was also significantly lower than that observed at 20 s. That is, a partial recovery (ϳ65%) of coupling between MOR and Ca 2ϩ channels was evident after the recovery period. Although the ability of morphine to cause MOR internalization is known to be poor, it shows a tendency to cause receptor desensitization and eventual tolerance (Arttamangkul et al 2008;Borgland et al 2003;Connor et al 2004;Dang and Williams 2005;Samoriski and Gross 2000;Yu et al 2009). The incomplete recovery may be explained by the receptor activity versus endocytosis (RAVE) model, which proposes that in the continued presence of morphine, cells are capable of eliciting adaptive mechanisms that oppose the actions of the activated MOR (Waldhover et al 2004;Whistler et al 1999).…”

Section: Discussionmentioning

confidence: 99%

Muscarinic Acetylcholine Receptor Modulation of Mu (μ) Opioid Receptors in Adult Rat Sphenopalatine Ganglion Neurons

Margas

Mahmoud

Ruiz‐Velasco

2010

Journal of Neurophysiology

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Margas W, Mahmoud S, Ruiz-Velasco V. Muscarinic acetylcholine receptor modulation of Mu () opioid receptors in adult rat sphenopalatine ganglion neurons. J Neurophysiol 103: 172-182, 2010. First published November 4, 2009 doi:10.1152/jn.00295.2009. The sphenopalatine ganglion (SPG) neurons represent the parasympathetic branch of the autonomic nervous system involved in controlling cerebral blood flow. In the present study, we examined the coupling mechanism between mu () opioid receptors (MOR) and muscarinic acetylcholine receptors (mAChR) with Ca 2ϩ channels in acutely dissociated adult rat SPG neurons. Successful MOR activation was recorded in ϳ40 -45% of SPG neurons employing the whole cell variant of the patch-clamp technique. In addition, immunofluorescence assays indicated that MOR are not expressed in all SPG neurons while M 2 mAChR staining was evident in all neurons. The concentration-response relationships generated with morphine and [d-Ala2-N-Me-Phe4-Glycol5]-enkephalin (DAMGO) showed IC 50 values of 15.2 and 56.1 nM and maximal Ca 2ϩ current inhibition of 26.0 and 38.7%, respectively. Activation of MOR or M 2 mAChR with morphine or oxotremorine-methiodide (Oxo-M), respectively, resulted in voltage-dependent inhibition of Ca 2ϩ currents via coupling with G␣ i/o protein subunits. The acute prolonged exposure (10 min) of neurons to morphine or Oxo-M led to the homologous desensitization of MOR and M 2 mAChR, respectively. The prolonged stimulation of M 2 mAChR with Oxo-M resulted in heterologous desensitization of morphine-mediated Ca 2ϩ current inhibition, and was sensitive to the M 2 mAChR blocker methoctramine. On the other hand, when the neurons were exposed to morphine or DAMGO for 10 min, heterologous desensitization of M 2 mAChR was not observed. These results suggest that in rat SPG neurons activation of M 2 mAChR likely modulates opioid transmission in the brain vasculature to adequately maintain cerebral blood flow.

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Differential Activation and Trafficking of μ-Opioid Receptors in Brain Slices

Cited by 99 publications

References 36 publications

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

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

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

Muscarinic Acetylcholine Receptor Modulation of Mu (μ) Opioid Receptors in Adult Rat Sphenopalatine Ganglion Neurons

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