The Delta Opioid Receptor in Pain Control

Abdallah, Khaled; Gendron, Louis

doi:10.1007/164_2017_32

Cited by 26 publications

(16 citation statements)

References 178 publications

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“…3B). Furthermore, since DOPr activation is associated with antinociceptive properties in mice (3,4,8), we characterized the nociceptive behavioral response to thermal stimuli. Using the complete Freund's adjuvant (CFA) chronic pain model, our data showed similar thermal antihyperalgesic effects in WT and KI animals following intrathecal administration of 1 μg of Deltorphin II (DLT II) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Belonging to the rhodopsin-like class A family of GPCRs, the δ-opioid receptor (DOPr) induces analgesic effects and attenuates pain hypersensitivities in several chronic pain models including neuropathic, inflammatory, diabetic, and cancer pain (3,4), while producing considerably less undesired effects than most clinical opioid therapeutics (5)(6)(7). Moreover, DOPr activation has been associated with anxiolytic, antidepressant, as well as cardioprotective and neuroprotective effects, thus rendering it an attractive therapeutic target for chronic pain management (8).…”

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confidence: 99%

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In vivo mapping of a GPCR interactome using knockin mice

Degrandmaison

Abdallah

Blais

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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With over 30% of current medications targeting this family of proteins, G-protein–coupled receptors (GPCRs) remain invaluable therapeutic targets. However, due to their unique physicochemical properties, their low abundance, and the lack of highly specific antibodies, GPCRs are still challenging to study in vivo. To overcome these limitations, we combined here transgenic mouse models and proteomic analyses in order to resolve the interactome of the δ-opioid receptor (DOPr) in its native in vivo environment. Given its analgesic properties and milder undesired effects than most clinically prescribed opioids, DOPr is a promising alternative therapeutic target for chronic pain management. However, the molecular and cellular mechanisms regulating its signaling and trafficking remain poorly characterized. We thus performed liquid chromatography–tandem mass spectrometry (LC-MS/MS) analyses on brain homogenates of our newly generated knockin mouse expressing a FLAG-tagged version of DOPr and revealed several endogenous DOPr interactors involved in protein folding, trafficking, and signal transduction. The interactions with a few identified partners such as VPS41, ARF6, Rabaptin-5, and Rab10 were validated. We report an approach to characterize in vivo interacting proteins of GPCRs, the largest family of membrane receptors with crucial implications in virtually all physiological systems.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

In vivo mapping of a GPCR interactome using knockin mice

Degrandmaison

Abdallah

Blais

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Nagase and Saitoh 2020) (Abdallah and Gendron 2018). NOP ligands have complicated effects on analgesia, depending on route of administration, and can modulate signaling by other opioid receptors (Cremeans et al 2012;Toll et al 2016;Varty et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Abuse liability, antinociceptive, and discriminative stimulus properties of IBNtxA

Islam¹,

Rahman²,

Brenner³

et al. 2020

Preprint

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Rationale: IBNtxA (3-iodobenzoyl naltrexamine) is a novel μ opioid receptor (MOR) agonist structurally related to the classical MOR antagonist naltrexone. Recent studies suggest IBNtxA preferentially signals through truncated MOR splice variants, producing a unique pharmacological profile resulting in antinociception with reduced side effects, including no conditioned place preference (CPP) when tested at a single dose. IBNtxA represents an intriguing lead compound for preclinical drug development targeting truncated MOR splice variants but further evaluation of its in vivo pharmacological profile is necessary to evaluate its potential.Objective: The purpose of this study was to independently verify the antinociceptive properties of IBNtxA and to more completely examine the rewarding properties and discriminative stimulus effects of IBNtxA. These results will allow broader assessment of IBNtxA as a translational candidate or lead compound for further development.Results: IBNtxA was synthesized and compared to morphine in a variety of mouse behavioral assays. 3 mg/kg IBNtxA was equipotent to 10 mg/kg morphine in a hot plate analgesia assay. In drug discrimination testing using mice trained to discriminate between 3 mg/kg IBNtxA and DMSO/saline vehicle, the κ agonist U-50488 fully substituted for IBNtxA. Classical μ agonist morphine, δ agonist SNC162, NOP agonist SCH 221510, and μ/NOP partial agonist buprenorphine each partially substituted for IBNtxA. IBNtxA up to 3 mg/kg did not produce a place preference in CPP. Pretreatment with 3 mg/kg IBNtxA but not 1 mg/kg IBNtxA attenuated acquisition of place preference for 10 mg/kg morphine. 3 mg/kg IBNtxA attenuated morphine-induced hyperlocomotion but did not alter naloxone-precipitated morphine withdrawal. Conclusions:Overall IBNtxA has a complicated opioid receptor pharmacology in vivo. These results indicate that IBNtxA produces potent antinociception and has low abuse liability, likely driven by substantial κ agonist signaling effects.

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“…Delta opioid receptors clearly exert a regulatory role. 152 Intrathecal delta preferring agonist such as DADL has analgesic efficacy in humans after intrathecal delivery. 154 Two non-peptide molecules ADL5747 and ADL5859 were two orally bioavailable compounds 155 tested for acute (NCT00993863) and chronic (NCT00979953) pain management in Phase 2 clinical trials but were not more effective than placebo in osteoarthritic patients.…”

Section: Survey Of Current Targets Of Pain Therapeuticsmentioning

confidence: 99%

Basic/Translational Development of Forthcoming Opioid- and Nonopioid-Targeted Pain Therapeutics

Knezevic

Yekkirala

Yaksh

2017

Anesthesia &Amp; Analgesia

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Opioids Opioids represent an efficacious therapeutic modality for some, but not all pain states. Singular reliance on opioid therapy for pain management, has limitations and abuse potential has deleterious consequences for patient and society. Our understanding of pain biology has yielded insights and opportunities for alternatives to conventional opioid agonists. The aim is to have efficacious therapies, with acceptable side effect profiles and minimal abuse potential, which is to say an absence of re-enforcing activity in the absence of a pain state. The present work provides a non-exclusive overview of current drug targets and potential future directions of research and development. We discuss channels activators and blockers, including: sodium channel blockers, potassium channel activators and calcium channel blockers; glutamate receptor targeted agents, including: NMDA, AMPA and metabotropic receptors). Further, we discuss therapeutics targeted at GABA, alpha2 adrenergic and opioid receptors. We also considered antagonists of angiotensin 2 and Toll receptors, and agonists/antagonists of adenosine, purine receptors. And cannabinoids. Novel targets considered are those focusing on lipid mediators and anti-inflammatory cytokines. Of interest is development of novel targeting strategies which produce long-term alterations in pain signaling, including viral transfection and toxins. We consider issues in the development of drugable molecules, including preclinical screening. While there are examples of successful translation, mechanistically promising pre-clinical candidates may unexpectedly fail during clinical trials because the preclinical models may not recapitulate the particular human pain condition being addressed. Molecular target characterization can diminish the disconnect between preclinical and humans’ targets, which should assist in developing non-addictive analgesics.

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The Delta Opioid Receptor in Pain Control

Cited by 26 publications

References 178 publications

In vivo mapping of a GPCR interactome using knockin mice

In vivo mapping of a GPCR interactome using knockin mice

Abuse liability, antinociceptive, and discriminative stimulus properties of IBNtxA

Basic/Translational Development of Forthcoming Opioid- and Nonopioid-Targeted Pain Therapeutics

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