Two delta opioid receptor subtypes are functional in single ventral tegmental area neurons, and can interact with the mu opioid receptor

Margolis, Elyssa B.; Fujita, Wakako; Devi, Lakshmi A.; Fields, Howard L.

doi:10.1016/j.neuropharm.2017.06.019

Cited by 38 publications

(38 citation statements)

References 75 publications

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“…Furthermore, the formation of MOR-DOR heteromers in native tissue may be both cell-dependent and systemdependent. 18,40 Demonstration of a unique pharmacologic profile is one of the key requirements for recognition of heteromer formation in native systems. 41,42 Several observations outlined in this study indicate that MOR and DOR are unlikely to function as a heteromer in the ENS.…”

Section: Lack Of Evidence For Heteromerization Of Mor and Dor In The Ensmentioning

confidence: 99%

“…In this study, MOR-induced hyperpolarization was enhanced in the presence of selective DOR antagonists. 40 However, this may be an overinterpretation because there was a population of myenteric neurons that expressed only MOR or DOR. Therefore, we used additional approaches to examine whether MOR-DOR heteromers exist in the colon.…”

Section: Lack Of Evidence For Heteromerization Of Mor and Dor In The Ensmentioning

confidence: 99%

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Mu and Delta Opioid Receptors Are Coexpressed and Functionally Interact in the Enteric Nervous System of the Mouse Colon

DiCello

Carbone

Saito

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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G protein-coupled receptors physically and functionally interact, leading to unique signaling. We report that delta and mu opioid receptors are coexpressed and functionally interact in myenteric neurons. Our findings have implications for opioid-based therapies for motility disorders and pain. BACKGROUND & AIMS:Functional interactions between the mu opioid receptor (MOR) and delta opioid receptor (DOR) represent a potential target for novel analgesics and may drive the effects of the clinically approved drug eluxadoline for the treatment of diarrhea-predominant irritable bowel syndrome. Although the enteric nervous system (ENS) is a likely site of action, the coexpression and potential interaction between MOR and DOR in the ENS are largely undefined. In the present study, we have characterized the distribution of MOR in the mouse ENS and examined MOR-DOR interactions by using pharmacologic and cell biology techniques.METHODS: MOR and DOR expression was defined by using MORmCherry and MORmCherry-DOR-eGFP knockin mice. MOR-DOR interactions were assessed by using DOR-eGFP internalization assays and by pharmacologic analysis of neurogenic contractions of the colon. RESULTS:Although MOR was expressed by approximately half of all myenteric neurons, MOR-positive submucosal neurons were rarely observed. There was extensive overlap between MOR and DOR in both excitatory and inhibitory pathways involved in the coordination of intestinal motility. MOR and DOR can functionally interact, as shown through heterologous desensitization of MORdependent responses by DOR agonists. Functional evidence suggests that MOR and DOR may not exist as heteromers in the ENS. Pharmacologic studies show no evidence of cooperativity between MOR and DOR. DOR internalizes independently of MOR in myenteric neurons, and MOR-evoked contractions are unaffected by the sequestration of DOR. CONCLUSIONS:Collectively, these findings demonstrate that although MOR and DOR are coexpressed in the ENS and functionally interact, they are unlikely to exist as heteromers under physiological conditions. (Cell Mol Gastroenterol Hepatol 2020;9:465-483; https://doi.

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Section: Lack Of Evidence For Heteromerization Of Mor and Dor In The Ensmentioning

confidence: 99%

Section: Lack Of Evidence For Heteromerization Of Mor and Dor In The Ensmentioning

confidence: 99%

Mu and Delta Opioid Receptors Are Coexpressed and Functionally Interact in the Enteric Nervous System of the Mouse Colon

DiCello

Carbone

Saito

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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“…Super-saturating concentrations of the MOR selective agonist DAMGO (10 μM) or the DOR selective agonist DPDPE (10 μM) were pressure ejected onto VTA neurons in the same manner as U-69,593. We have previously shown that DAMGO and DPDPE responses in VTA neurons in acute brain slices do not desensitize [3,4]. In responsive neurons, the agonist was re-applied after 10 nM of either KOR antagonist had been bath applied for at least 4 min.…”

Section: Resultsmentioning

confidence: 99%

Differential effects of novel kappa opioid receptor antagonists on dopamine neurons using acute brain slice electrophysiology

Margolis

Wallace

Orden

et al. 2020

Preprint

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19Activation of the kappa opioid receptor (KOR) contributes to the aversive properties of 20 stress, and modulates key neuronal circuits underlying many neurobehavioral disorders. KOR 21 agonists directly inhibit ventral tegmental area (VTA) dopaminergic neurons, contributing to 22 aversive responses [1,2]; therefore, selective KOR antagonists represent a novel therapeutic 23 approach to restore circuit function. We used whole cell electrophysiology in acute rat midbrain 24 slices to evaluate pharmacological properties of four novel KOR antagonists: BTRX-335140, 25 BTRX-395750, PF-04455242, and JNJ-67953964. Each compound concentration-dependently 26 reduced the outward current induced by the KOR selective agonist U-69,593. BTRX-335140 and 27 BTRX-395750 fully blocked U-69,593 currents (IC 50 = 1.3 ± 0.9 and 4.6 ± 0.9 nM, respectively).28 JNJ-67953964 showed an IC 50 of 0.3 ± 1.3 nM. PF-04455242 (IC 50 = 19.6 ± 16 nM) exhibited 29 partial antagonist activity (~60% maximal blockade). In 50% of neurons, 1 M PF-04455242 30 generated an outward current independent of KOR activation. BTRX-335140 (10 nM) did not 31 affect responses to saturating concentrations of the mu opioid receptor (MOR) agonist DAMGO 32 or the delta opioid receptor (DOR) agonist DPDPE, while JNJ-67953964 (10 nM) partially blocked 33 DAMGO responses and had no effect on DPDPE responses. Importantly, BTRX-335140 (10 nM) 34 rapidly washed out with complete recovery of U-69,593 responses within 10 min. Collectively, we 35 show electrophysiological evidence of key differences amongst KOR antagonists that could 36 impact their therapeutic potential and have not been observed using recombinant systems. The 37 results of this study demonstrate the value of characterizing compounds in native neuronal tissue 38 and within disorder-relevant circuits implicated in neurobehavioral disorders. Introduction 40One of the major challenges in drug development is predicting whole animal responses 42 indicate that the effect of drugs on G protein coupled receptor function in situ in brain tissue is not 43 reliably predicted from results in expression systems [3][4][5][6][7][8]. Therefore pharmacological 44 characterizations made in brain tissue likely relate better to behavioral outcomes than those made 45 in cell-based expression assays. 46Interest in the kappa opioid receptor (KOR) as a target for therapeutic development has 47 been growing consistently as clinical and preclinical studies have identified its role in aversive 48 behavioral states. KOR agonists produce profound adverse effects in humans, specifically 49 fatigue, sedation, confusion, impaired concentration, and anxiety. Furthermore at higher 50 concentrations visual and auditory hallucinations and feelings of depersonalization have been 51 reported [9,10]. Homologous effects have been described in animal models (reviewed in [11]). 52 Finally, blockade or genetic deletion of the KOR significantly reduces aversive responses to stress 53 [12-14], drug withdrawal [15-17], and pain [18], and has antidepres...

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“…In the ventral tegmental area where the two receptors functionally interact, increased G protein dependent K + conductance in response to DPDPE or deltorphin II was observed in the presence of the mu antagonist CTAP. Conversely the delta antagonist TIPPψ enhanced DAMGO evoked responses (Margolis et al 2017) suggesting that mu-delta functional interactions blunt this signalling pathway in vivo.…”

Section: Activation Of Endogenous Mu-delta Heteromers Promotes Sustaimentioning

confidence: 99%

“…In VTA slices, co-application of the delta antagonist TIPPψ together with the mu agonist DAMGO or co-application of the mu antagonist CTAP together with the delta agonists deltorphin II or DPDPE strongly suggested that mu-delta receptor heteromerization decreases opioid signal transduction (Margolis et al 2017). In addition, constitutive recruitment of βarrestin 2 by mu-delta heteromers was observed in SKNSH neuroblastoma cells that affected ERK1/2 signaling ).…”

Section: Introductionmentioning

confidence: 99%

Heteromerization of endogenous mu and delta opioid receptors tunes mu opioid receptor signaling and trafficking

Derouiche¹,

Ugur²,

Pierre³

et al. 2018

Preprint

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Increasing evidence indicates that native mu and delta opioid receptors can associate to form heteromers in discrete brain neuronal circuits. However, little is known about their signaling and trafficking. Using double fluorescent knock-in mice, we investigated the impact of neuronal co-expression on the internalization profile of mu and delta opioid receptors in primary hippocampal cultures and in vivo. We established ligand selective mu-delta cointernalization upon activation by exogenous ligands and provide evidence for mu-delta cointernalization by the endogenous opioid peptide met-enkephalin, but not β-endorphin. Cointernalization was driven by the delta opioid receptor, required an active conformation of both receptors and led to sorting to the lysosomal compartment. This alteration in the mu opioid receptor intracellular fate was accompanied by sustained ERK1/2 phosphorylation. In addition, increased mu-delta neuronal co-localization in the rostral ventromedial medulla in a chronic neuropathic state suggests that mu-delta heteromers are involved in the regulation of nociceptive transmission Keywords G protein-coupled receptors, opioid receptor, heteromers, internalization, ERK phosphorylation, neuropathic pain, fluorescent knock-in mice, endogenous opioid peptides, hippocampus, rostral ventromedial medulla

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Two delta opioid receptor subtypes are functional in single ventral tegmental area neurons, and can interact with the mu opioid receptor

Cited by 38 publications

References 75 publications

Mu and Delta Opioid Receptors Are Coexpressed and Functionally Interact in the Enteric Nervous System of the Mouse Colon

Mu and Delta Opioid Receptors Are Coexpressed and Functionally Interact in the Enteric Nervous System of the Mouse Colon

Differential effects of novel kappa opioid receptor antagonists on dopamine neurons using acute brain slice electrophysiology

Heteromerization of endogenous mu and delta opioid receptors tunes mu opioid receptor signaling and trafficking

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