Molecular Pharmacology of<i>δ</i>-Opioid Receptors

Gendron, Louis; Cahill, Catherine M.; Zastrow, Mark von; Schiller, Peter W.; Piñeyro, Graciela

doi:10.1124/pr.114.008979

Cited by 104 publications

(112 citation statements)

References 750 publications

(1,037 reference statements)

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“…We focused on DOR because of an open and unresolved question regarding the molecular and cellular basis of its downregulation. DOR down-regulation by endocytic trafficking to lysosomes is physiologically important and contributes to the development of tolerance to opioid analgesic drugs in vivo (Gendron et al, 2016). Mechanistically, lysosomal downregulation typically requires transmembrane proteins to engage the ubiquitin network in endosomes (Schmidt and Teis, 2012).…”

Section: Resultsmentioning

confidence: 99%

An Approach to Spatiotemporally Resolve Protein Interaction Networks in Living Cells

Lobingier

Hüttenhain

Eichel

et al. 2017

Cell

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325

334

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SUMMARY Cells operate through protein interaction networks organized in space and time. Here, we describe an approach to resolve both dimensions simultaneously by using proximity labeling mediated by engineered ascorbic acid peroxidase (APEX). APEX has been used to capture entire organelle proteomes with high temporal resolution, but its breadth of labeling is generally thought to preclude the higher spatial resolution necessary to interrogate specific protein networks. We provide a solution to this problem by combining quantitative proteomics with a system of spatial references. As proof of principle, we apply this approach to interrogate proteins engaged by G-protein-coupled receptors as they dynamically signal and traffic in response to ligand-induced activation. The method resolves known binding partners, as well as previously unidentified network components. Validating its utility as a discovery pipeline, we establish that two of these proteins promote ubiquitin-linked receptor downregulation after prolonged activation.

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Section: Resultsmentioning

confidence: 99%

An Approach to Spatiotemporally Resolve Protein Interaction Networks in Living Cells

Lobingier

Hüttenhain

Eichel

et al. 2017

Cell

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325

334

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“…The MOPs mediate the canonical effects of clinically used opioids, namely analgesia, euphoria, respiratory depression, and constipation. Activation of the δ-opioid receptor (DOP) also produces analgesia in chronic pain states, and agonists are being developed by industry for the treatment of anxiety and migraine [6,7]. κ-Opioid receptor (KOP) agonists elicit anxiogenic and dysphoric effects, and are notable for exhibiting opposing effects to MOP agonists on emotional regulation [8].…”

Section: What Is Tolerance?mentioning

confidence: 99%

Allostatic Mechanisms of Opioid Tolerance Beyond Desensitization and Downregulation

Cahill

Walwyn

Taylor

et al. 2016

Trends in Pharmacological Sciences

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Mechanisms of opioid tolerance have focused on adaptive modifications within cells containing opioid receptors, defined here as cellular allostasis, emphasizing regulation of the opioid receptor signalosome. We review additional regulatory and opponent processes involved in behavioral tolerance, and include mechanistic differences both between agonists (agonist bias), and between μ- and δ-opioid receptors. In a process we will refer to as pass-forward allostasis, cells modified directly by opioid drugs impute allostatic changes to downstream circuitry. Because of the broad distribution of opioid systems, every brain cell may be touched by pass-forward allostasis in the opioid-dependent/tolerant state. We will implicate neurons and microglia as interactive contributors to the cumulative allostatic processes creating analgesic and hedonic tolerance to opioid drugs.

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“…␦R expressed in nociceptive neurons can reduce cAMP and inhibit Ca 2ϩ channels to inhibit neuronal activity (Jutkiewicz et al, 2006;Cahill et al, 2007;Pradhan et al, 2011;Bardoni et al, 2014). ␦R agonists can cause antinociception in some conditions, and they show reduced abuse liability compared with current opioids that target the opioid receptor (R) ( Vanderah, 2010;Gendron et al, 2016). ␦R-mediated antinociception in vivo, however, requires high doses approaching concentrations that cause serious adverse effects (Danielsson et al, 2006;Jutkiewicz et al, 2006;Pradhan et al, 2011;Gendron et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…␦R agonists can cause antinociception in some conditions, and they show reduced abuse liability compared with current opioids that target the opioid receptor (R) ( Vanderah, 2010;Gendron et al, 2016). ␦R-mediated antinociception in vivo, however, requires high doses approaching concentrations that cause serious adverse effects (Danielsson et al, 2006;Jutkiewicz et al, 2006;Pradhan et al, 2011;Gendron et al, 2016). This low agonist efficacy is a critical limiting factor in developing ␦R as a drug target.…”

Section: Introductionmentioning

confidence: 99%

A PTEN-Regulated Checkpoint Controls Surface Delivery of δ Opioid Receptors

et al. 2017

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The ␦ opioid receptor (␦R) is a promising alternate target for pain management because ␦R agonists show decreased abuse potential compared with current opioid analgesics that target the opioid receptor. A critical limitation in developing ␦R as an analgesic target, however, is that ␦R agonists show relatively low efficacy in vivo, requiring the use of high doses that often cause adverse effects, such as convulsions. Here we tested whether intracellular retention of ␦R in sensory neurons contributes to this low ␦R agonist efficacy in vivo by limiting surface ␦R expression. Using direct visualization of ␦R trafficking and localization, we define a phosphatase and tensin homolog (PTEN)-regulated checkpoint that retains ␦R in the Golgi and decreases surface delivery in rat and mice sensory neurons. PTEN inhibition releases ␦R from this checkpoint and stimulates delivery of exogenous and endogenous ␦R to the neuronal surface both in vitro and in vivo. PTEN inhibition in vivo increases the percentage of TG neurons expressing ␦R on the surface and allows efficient ␦R-mediated antihyperalgesia in mice. Together, we define a critical role for PTEN in regulating the surface delivery and bioavailability of the ␦R, explain the low efficacy of ␦R agonists in vivo, and provide evidence that active ␦R relocation is a viable strategy to increase ␦R antinociception.

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Molecular Pharmacology ofδ-Opioid Receptors

Cited by 104 publications

References 750 publications

An Approach to Spatiotemporally Resolve Protein Interaction Networks in Living Cells

An Approach to Spatiotemporally Resolve Protein Interaction Networks in Living Cells

Allostatic Mechanisms of Opioid Tolerance Beyond Desensitization and Downregulation

A PTEN-Regulated Checkpoint Controls Surface Delivery of δ Opioid Receptors

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