Molecular Mechanisms and Regulation of Opioid Receptor Signaling

Law, Ping Yee; Wong, Yung Hou; Loh, Horace H.

doi:10.1146/annurev.pharmtox.40.1.389

Cited by 585 publications

(445 citation statements)

References 218 publications

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“…However, the chronic effects of cocaine on the cdk5/p35 complex (upregulation) were mediated through the induction of the transcription factor DFosB (Bibb et al, 2001), and the accumulation of DFosB in brain also has been observed after chronic morphine administration (Nye and Nestler, 1996;Nestler et al, 2001). Owing to the multiple and complex opioid receptor signaling (Law et al, 2000), different molecular mechanisms may account for the downregulation of the cdk5/p35 complex induced by chronic morphine exposure.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Neuronal cdk5/p35 in Opioid Addicts and Opiate-Treated Rats: Relation to Neurofilament Phosphorylation

Ferrer-Alcón

Harpe

Guimón

et al. 2002

Neuropsychopharmacol

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Neuronal cyclin-dependent kinase-5 (Cdk5) and its neuron-specific activator p35 play a major role in regulating the cytoskeleton dynamics. Since opioid addiction was associated with hyperphosphorylation of neurofilament (NF) in postmortem human brains, this study was undertaken to assess the status of the cdk5/p35 complex and its relation with NF-H phosphorylation in brains of chronic opioid abusers. Decreased immunodensities of cdk5 (18%) and p35 (26-44%) were found in the prefrontal cortex of opioid addicts compared with matched controls. In the same brains, the densities of p25 (a truncated neurotoxic form of p35), phosphatase PP2Ac and m-calpain were found unaltered. Acute treatment of rats with morphine (30 mg/kg, 2 h) increased the density of cdk5 (35%), but not that of p35, in the cerebral cortex. In contrast, chronic morphine (10-100 mg/kg for 5 days) induced marked decreases in cdk5 (40%) and p35 (47%) in rat brain. In brains of opioid addicts, the density of phosphorylated NF-H was increased (43%) as well as the ratio of phosphorylated to nonphosphorylated NF-H forms (two-fold). In these brains, phosphorylated NF-H significantly correlated with p35 (r ¼ 0.58) but not with cdk5 (r ¼ 0.03). The results suggest that opiate addiction is associated with downregulation of cdk5/p35 levels in the brain. This downregulation and the aberrant hyperphosphorylation of NF-H proteins might have important consequences in the development of neural plasticity associated with opiate addiction in humans.

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Section: Discussionmentioning

confidence: 99%

Downregulation of Neuronal cdk5/p35 in Opioid Addicts and Opiate-Treated Rats: Relation to Neurofilament Phosphorylation

Ferrer-Alcón

Harpe

Guimón

et al. 2002

Neuropsychopharmacol

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“…They are coupled via pertussis toxin-sensitive G i /G o proteins to a variety of effectors that include adenylate cyclase, potassium channels, calcium channels, and mitogen-activated protein kinase pathways {for a review, see [2]}. Morphine acts primarily on the MOR [3] and are among the most widely abused drugs.…”

Section: Introductionmentioning

confidence: 99%

Brain region-specific N-glycosylation and lipid rafts association of the rat mu opioid receptor

Huang

Chen

et al. 2008

Biochemical and Biophysical Research Communications

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The mu opioid receptor (MOR) in the rat and mouse caudate putamen (CPu) and thalamus was demonstrated as diffuse and broad bands by western blot with polyclonal antibodies against a Cterminal peptide of MOR, which were absent in the cerebellum and brains of MOR-knockout mice. The electrophoretic mobility of MOR differed in the two brain regions with median relative molecular masses (Mr's) of 75 kDa (CPu) vs. 66 kDa (thalamus) for the rat, and 74 kDa (CPu) vs. 63 kDa (thalamus) for the mouse, which was due to its differential N-glycosylation. Rat MOR in CPu was found mainly associated with low-density cholesterol-and ganglioside M1 (GM1)-enriched fractions (lipid rafts), while the MOR in the thalamus was present in rafts and non-rafts without preference. Cholesterol reduction by methyl-β-cyclodextrin decreased DAGMO-induced [ 35 S]GTPγS binding in rat CPu membranes to a greater extent than in the thalamus membranes.

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“…These receptors belong to rhodopsin subfamily of 7-transmembrane receptors (7-TMRs)/G-protein-coupled receptors (GPCRs) (Bockaert and Pin, 1999). They are coupled via pertussis toxin-sensitive G i /G o proteins to many downstream effectors such as adenylate cyclase, potassium channels, calcium channels, and a mitogen-activated protein kinase pathway [for a review, see Law et al, 2000]. Although opioid drugs have long been used as analgesics, their clinical use is limited by the fear of addiction and side effects such as respiratory depression, decreased gastrointestinal motility, sedation, mood changes, and tolerance (Kieffer, 1999).…”

Section: Introductionmentioning

confidence: 99%

Agonist treatment did not affect association of mu opioid receptors with lipid rafts and cholesterol reduction had opposite effects on the receptor-mediated signaling in rat brain and CHO cells

Huang

Yoon

et al. 2007

Brain Research

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Lipid rafts are small cholesterol-and glycosphingolipid-enriched membrane subdomains. Here we compared the mu opioid receptor (MOR)-lipid rafts relationship in the rat brain, where neurons have non-caveolae rafts, and in CHO cells stably transfected with HA-rat MOR (CHO-HArMOR), which are enriched in caveolae. Membranes of rat caudate putamen (CPu) and thalamus or CHO-HA-rMOR cells were homogenized, sonicated in a detergent-free 0.5 M Na 2 CO 3 buffer and fractionated through sucrose density gradients. Western blot and [ 3 H]diprenorphine binding showed that ~70% of MOR in CHO-HA-rMOR was present in low-density (5-20% sucrose) fractions enriched in cholesterol and/or ganglioside M1 (GM1) (lipid rafts) in plasma membranes, whereas about 70% and 45% of MOR in CPu and thalamus, respectively, were associated with lipid rafts. Incubation with a saturating concentration of etorphine or morphine at 37 °C for 30 min failed to change the MOR location in rafts in CHO-HA-rMOR, indicating that the internalized MOR does not move out of rafts, in contrast to the delta opioid receptor. In vivo, rafts association of MOR in CPu and thalamus was not affected significantly in rats implanted with two 75-mg morphine pellets for 72 h. In addition, cholesterol reduction by methyl-β-cyclodextrin (MCD) disrupted rafts and shifted MOR to higher density fractions in both CHO-HA-rMOR and CPu membranes. However, MCD treatment had opposite impacts on MOR signaling in the two tissues: it attenuated MOR-mediated [ 35 S]GTPγS binding in CPu but enhanced it in CHO-HA-rMOR.

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Molecular Mechanisms and Regulation of Opioid Receptor Signaling

Cited by 585 publications

References 218 publications

Downregulation of Neuronal cdk5/p35 in Opioid Addicts and Opiate-Treated Rats: Relation to Neurofilament Phosphorylation

Downregulation of Neuronal cdk5/p35 in Opioid Addicts and Opiate-Treated Rats: Relation to Neurofilament Phosphorylation

Brain region-specific N-glycosylation and lipid rafts association of the rat mu opioid receptor

Agonist treatment did not affect association of mu opioid receptors with lipid rafts and cholesterol reduction had opposite effects on the receptor-mediated signaling in rat brain and CHO cells

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