Tolerance to high‐internalizing δ opioid receptor agonist is critically mediated by arrestin 2

Vicente-Sánchez, Ana; Dripps, Isaac; Tipton, Alycia F; Akbari, Heba; Akbari, Areeb; Jutkiewicz, Emily M.; Pradhan, Amynah

doi:10.1111/bph.14353

Cited by 40 publications

(40 citation statements)

References 55 publications

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“…We observed no change in the analgesic efficacy of PN6047 over a 16-day dosing regimen. For comparison, a recent study reported that repeated treatment of mice (once daily; 10 mg/kg) with SNC80 resulted in analgesic tolerance within 3 days (Vicente-Sanchez et al, 2018). The lack of tolerance to PN6047 may in part arise as a consequence of its limited ability to induce internalization.…”

Section: Discussionmentioning

confidence: 99%

A Novel G Protein–Biased Agonist at the δ Opioid Receptor with Analgesic Efficacy in Models of Chronic Pain

Conibear

Asghar

Hill

et al. 2019

J Pharmacol Exp Ther

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Agonists at the d opioid receptor are known to be potent antihyperalgesics in chronic pain models and effective in models of anxiety and depression. However, some d opioid agonists have proconvulsant properties while tolerance to the therapeutic effects can develop. Previous evidence indicates that different agonists acting at the d opioid receptor differentially engage signaling and regulatory pathways with significant effects on behavioral outcomes. As such, interest is now growing in the development of biased agonists as a potential means to target specific signaling pathways and potentially improve the therapeutic profile of d opioid agonists. Here, we report on PN6047 (3-[[4-(dimethylcarbamoyl)phenyl]-[1-(thiazol-5-ylmethyl)-4piperidylidene]methyl]benzamide), a novel G protein-biased and selective d opioid agonist. In cell-based assays, PN6047 fully engages G protein signaling but is a partial agonist in both the arrestin recruitment and internalization assays. PN6047 is effective in rodent models of chronic pain but shows no detectable analgesic tolerance following prolonged treatment. In addition, PN6047 exhibited antidepressant-like activity in the forced swim test, and importantly, the drug had no effect on chemically induced seizures. PN6047 did not exhibit reward-like properties in the conditioned place preference test or induce respiratory depression. Thus, d opioid ligands with limited arrestin signaling such as PN6047 may be therapeutically beneficial in the treatment of chronic pain states. SIGNIFICANCE STATEMENT PN6047 (3-[[4-(dimethylcarbamoyl)phenyl]-[1-(thiazol-5-ylmethyl)-4piperidylidene]methyl]benzamide) is a selective, G protein-biased d opioid agonist with efficacy in preclinical models of chronic pain. No analgesic tolerance was observed after prolonged treatment, and PN6047 does not display proconvulsant activity or other opioidmediated adverse effects. Our data suggest that d opioid ligands with limited arrestin signaling will be beneficial in the treatment of chronic pain.

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Section: Discussionmentioning

confidence: 99%

A Novel G Protein–Biased Agonist at the δ Opioid Receptor with Analgesic Efficacy in Models of Chronic Pain

Conibear

Asghar

Hill

et al. 2019

J Pharmacol Exp Ther

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“…Over the last two decades, improved pharmacological characterization of opioid pathways has revealed that activation of an opioid receptor can trigger two distinct pathways, β-arrestin-dependent or β-arrestin-independent (i.e., G protein-mediated) and that these pathways differentially modulate antinociception and side effect profiles [9]. Despite the increasing number of studies that implicate δOR mediated β-arrestin recruitment with various (patho)physiological effects, such as tolerance [10], alcohol intake [11,12] and δOR agonist-induced seizures [10], the role of βarrestin recruitment towards δOR-induced cardioprotection remains unclear. From a translational perspective, peptide-based probes provide an ideal tool for studying the cardioprotective effects of the δOR, given their low brain penetration.…”

Section: Introductionmentioning

confidence: 99%

The Meta-Position of Phe4 in Leu-Enkephalin Regulates Potency, Selectivity, Functional Activity, and Signaling Bias at the Delta and Mu Opioid Receptors

Cassell

Sharma

et al. 2019

Molecules

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As tool compounds to study cardiac ischemia, the endogenous δ-opioid receptors (δOR) agonist Leu 5 -enkephalin and the more metabolically stable synthetic peptide (d-Ala 2 , d-Leu 5 )-enkephalin are frequently employed. However, both peptides have similar pharmacological profiles that restrict detailed investigation of the cellular mechanism of the δOR's protective role during ischemic events. Thus, a need remains for δOR peptides with improved selectivity and unique signaling properties for investigating the specific roles for δOR signaling in cardiac ischemia. To this end, we explored substitution at the Phe 4 position of Leu 5 -enkephalin for its ability to modulate receptor function and selectivity. Peptides were assessed for their affinity to bind to δORs and µ-opioid receptors (µORs) and potency to inhibit cAMP signaling and to recruit β-arrestin 2. Additionally, peptide stability was measured in rat plasma. Substitution of the meta-position of Phe 4 of Leu 5 -enkephalin provided high-affinity ligands with varying levels of selectivity and bias at both the δOR and µOR and improved peptide stability, while substitution with picoline derivatives produced lower-affinity ligands with G protein biases at both receptors. Overall, these favorable substitutions at the meta-position of Phe 4 may be combined with other modifications to Leu 5 -enkephalin to deliver improved agonists with finely tuned potency, selectivity, bias and drug-like properties.

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“…[12][13][14] As such, relatively few studies have systematically assessed this alternate pathway despite its important roles in regulating OR desensitization, and purported promotion of β-arrestin-dependent signal transduction through the scaffolding of various kinases. 15 An increasing number of studies have implicated δOR mediated β-arrestin recruitment with various (patho)physiological effects, ranging from tolerance, 16 alcohol intake 17,18 and δOR agonist-induced seizures. 16 To minimize these adverse effects, the development of "biased" ligands that can selectively activate the G protein pathway, without engaging the β-arrestinassociated pathways, 19 may provide a key set of pharmacological tools for reevaluating the drugability of δOR for several disease states.…”

Section: Introductionmentioning

confidence: 99%

“…15 An increasing number of studies have implicated δOR mediated β-arrestin recruitment with various (patho)physiological effects, ranging from tolerance, 16 alcohol intake 17,18 and δOR agonist-induced seizures. 16 To minimize these adverse effects, the development of "biased" ligands that can selectively activate the G protein pathway, without engaging the β-arrestinassociated pathways, 19 may provide a key set of pharmacological tools for reevaluating the drugability of δOR for several disease states.…”

Section: Introductionmentioning

confidence: 99%

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The Meta-Position of Phe⁴ in Leu-enkephalin Regulates Potency, Selectivity, Functional Activity, and Signaling Bias at the Delta and Mu Opioid Receptors

Cassell

Sharma

et al. 2019

Preprint

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Activation of an opioid receptor can trigger two distinct pathways (G protein coupling and arrestin recruitment) that differentially regulate a host of desired and undesired pharmacological effects. To explore the pharmacology of these pathways and to differentiate desired pharmacological effects from undesired side effects, "biased" ligands, those that selectively activate one pathway over the other, serve as useful tool compounds. Though an extensive array of biased ligands have been developed for exploring µ-opioid receptor pharmacology, few studies have explored biased ligands for the δ-opioid receptor, which is not associated with the detrimental side effects mediated by the µ-opioid receptor.Herein, we explore the Phe 4 position of the endogenous δ-opioid receptor ligand, Leuenkephalin (Tyr-Gly-Gly-Phe-Leu). Substitution of the meta-position of Phe 4 of Leu-enkephalin provides high-affinity ligands with varying levels of selectivity and bias at both the δ-opioid receptor and µ-opioid receptor, while substitution with picoline derivatives produced loweraffinity ligands with good biases at both receptors. Further, Phe 4 substitution also improves peptide stability relative to Leu-enkephalin. Overall, these favorable substitutions to the metaposition of Phe 4 might be combined with other modifications to Leu-enkephalin to deliver improved ligands with finely tuned potency, selectivity, bias and drug-like properties.

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Tolerance to high‐internalizing δ opioid receptor agonist is critically mediated by arrestin 2

Abstract: Overall, these results suggest that δ receptor agonists interact with arrestins in a ligand-specific manner, and tolerance to high- but not low-internalizing agonists are preferentially regulated by arrestin 2.

Cited by 40 publications

References 55 publications

A Novel G Protein–Biased Agonist at the δ Opioid Receptor with Analgesic Efficacy in Models of Chronic Pain

A Novel G Protein–Biased Agonist at the δ Opioid Receptor with Analgesic Efficacy in Models of Chronic Pain

The Meta-Position of Phe4 in Leu-Enkephalin Regulates Potency, Selectivity, Functional Activity, and Signaling Bias at the Delta and Mu Opioid Receptors

The Meta-Position of Phe⁴ in Leu-enkephalin Regulates Potency, Selectivity, Functional Activity, and Signaling Bias at the Delta and Mu Opioid Receptors

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Tolerance to high‐internalizing δ opioid receptor agonist is critically mediated by arrestin 2

Abstract: Overall, these results suggest that δ receptor agonists interact with arrestins in a ligand-specific manner, and tolerance to high- but not low-internalizing agonists are preferentially regulated by arrestin 2.

Cited by 40 publications

References 55 publications

A Novel G Protein–Biased Agonist at the δ Opioid Receptor with Analgesic Efficacy in Models of Chronic Pain

A Novel G Protein–Biased Agonist at the δ Opioid Receptor with Analgesic Efficacy in Models of Chronic Pain

The Meta-Position of Phe4 in Leu-Enkephalin Regulates Potency, Selectivity, Functional Activity, and Signaling Bias at the Delta and Mu Opioid Receptors

The Meta-Position of Phe4 in Leu-enkephalin Regulates Potency, Selectivity, Functional Activity, and Signaling Bias at the Delta and Mu Opioid Receptors

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The Meta-Position of Phe⁴ in Leu-enkephalin Regulates Potency, Selectivity, Functional Activity, and Signaling Bias at the Delta and Mu Opioid Receptors