Delta Receptor

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Stimulation of a GPCR by an extracellular ligand triggers receptor signaling via G proteins, and this process is highly regulated. Receptor activation is typically accompanied by desensitization of receptor signaling, a complex feedback regulatory process of which receptor internalization is postulated as a key event. The in vivo significance of GPCR internalization is poorly understood. In fact, the majority of studies have been performed in transfected cell systems, which do not adequately model physiological environments and the complexity of integrated responses observed in the whole animal.

In this study, we used knock-in mice expressing functional fluorescent delta opioid receptors DOR-eGFP in place of the native receptor to correlate receptor localization in neurons with behavioral responses. We analyzed the pain-relieving effects of two delta receptor agonists with similar signaling potencies and efficacies, but distinct internalizing properties. However, subsequent drug treatment produced highly distinct responses. Animals initially treated with SNC80 showed no analgesic response to a second dose of either delta receptor agonist. Concomitant receptor internalization and G-protein uncoupling were observed throughout the nervous system.

In contrast, treatment with AR-M resulted in retained analgesic response to a subsequent agonist injection, and ex vivo analysis showed that DOR-eGFP receptor remained G protein-coupled on the cell surface. Together our data show that delta agonists retain full analgesic efficacy when receptors remain on the cell surface. In contrast, delta agonist-induced analgesia is abolished following receptor internalization, and complete behavioral desensitization is observed. Overall these results establish that, in the context of pain control, receptor localization fully controls receptor function in vivo.

This finding has both fundamental and therapeutic implications for slow-recycling GPCRs. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist. G protein coupled receptors GPCRs form the largest family of membrane receptors [1]. A variety of physiological functions are regulated by GPCRs, which represent the most common target for therapeutic drugs. Stimulation of a GPCR by an extracellular messenger, either physiological or synthetic, triggers intracellular receptor signaling via heterotrimeric G proteins. This process is highly regulated and receptor activation is typically accompanied by desensitization of receptor signaling, a complex feedback regulatory process whereby receptor responsiveness decreases upon continued agonist stimulation.

Receptor trafficking is considered to be a key process in the regulation of receptor signaling. In particular, many studies have shown that receptor stimulation by an agonist concomitantly leads to receptor signaling and redistribution of receptor molecules away from the cell surface for review see [2] — [3]. The significance of receptor endocytosis in the regulation of GPCR function is under intense investigation, and many aspects deserve further clarification.

First, receptor internalization may influence agonist efficacy in different ways. The most straightforward hypothesis proposes that receptor internalization reduces agonist effects, as fewer receptors are available at the cell surface. On the contrary, it has also been suggested that receptor endocytosis promotes rapid resensitization by recycling the receptor back to the cell surface, which contributes to the maintenance of a large population of active receptors at the plasma membrane [4].

Second, receptor internalization may not simply terminate intracellular signaling.

How does the opioid system control pain, reward and addictive behavior?

Binding to these adaptor proteins initiates receptor internalization and physically prevents further receptor interaction with heterotrimeric G proteins. Third, the physiological relevance of many receptor trafficking studies is limited, as the majority have been performed in transfected cellular models. These in vitro systems may not reflect in vivo situations in terms of receptor density, protein content of receptor-expressing cells, or even receptor localization within subcellular compartments, as is the case for neurons [3].

Additionally, data from cellular models provide no understanding of how receptor trafficking influences integrated responses in the living organism. Fourth, individual GPCRs vastly differ in their trafficking properties, leading to specific regulatory mechanisms for each receptor.


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Overall, the characterization of receptor trafficking in native tissues is only beginning [7]. Due to limited availability of specific antibodies, in vivo trafficking of GPCRs has been investigated for only a limited number of native receptors [8] — [12]. Recently we have created knock-in mice expressing a fully functional fluorescent delta opioid receptor DOR-eGFP in place of the endogenous delta receptor.

Furthermore, these receptors are directly visible in vivo. These mutant mice have proven to be an exceptional tool in studying receptor neuroanatomy, real-time receptor trafficking in live neurons, and receptor movements in vivo [13]. This unique animal model can now be used to determine the relationship between receptor trafficking in neurons and receptor function at a behavioral level.

Our previous work using DOR-eGFP mice showed that treatment with the delta agonist SNC80 triggered massive receptor endocytosis throughout the nervous system, together with locomotor activation. We further showed that mice with internalized receptors did not show locomotor activation following a second drug administration [13].

δ-opioid receptor - Wikipedia

This was a first indication that internalization may impact delta receptor function in vivo , at least in the case of locomotor responses. The opioid system is involved in pain control, reward processing, and stress responses. Genetic approaches have revealed that the delta receptor fulfills roles highly distinct from those of mu and kappa opioid receptors [14] , [15].

Several studies have shown that delta receptors can specifically alleviate persistent pain [16] — [20]. In the present study we examine the regulation of delta opioid receptor function in the control of inflammatory pain. We show that the two compounds have very distinct internalizing properties, despite similar in vitro signaling potencies and efficacies. Further, we find in vivo that a first injection of each agonist in DOR-eGFP mice reduces inflammatory pain, with similar efficacy for the two drugs. Importantly, we find that a subsequent agonist administration in vivo has very distinct consequences on the behavioral response.

The high-internalizing agonist no longer relieves pain, indicating that acute in vivo desensitization has occurred. In contrast the low-internalizing agonist remains fully active following the second administration, demonstrating that non-internalized receptors remain functional. Finally, we show that receptor phosphorylation and uncoupling parallels receptor internalization, and that restoration of surface receptors reinstate opioid analgesia. These data unambiguously demonstrate that receptor internalization fully determines drug efficacy in vivo.

SNC80 [21] is a widely used non-peptidic compound that shows high delta selectivity in vivo , and was chosen as a reference delta receptor agonist in this study. Met-enkephalin was also examined ex vivo , as a prototypic endogenous delta opioid receptor agonist. We first characterized the pharmacological profiles of the three delta receptor agonists in brain membranes prepared from DOR-eGFP mice.

In competition binding experiments, all three ligands displaced [ 3 H]naltrindole with binding affinities in the nanomolar range Table 1. The two synthetic alkaloids, SNC80 and ARM, had affinities which were approximately 10 times greater than the affinity of Met-enkephalin. The three agonists had similar potencies. Data mainly from transfected cellular models [24] , and references therein , and also from in vivo experiments [12] , [25] , [26] , indicate that delta agonists trigger delta receptor internalization. Similar results were obtained for both neuronal preparations Table 1.


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A Representative images of hippocampal neurons treated with nM of agonists are shown. SNC80 is a high-internalizing agonist whereas ARM appears to be a low-internalizing agonist under ex vivo experimental conditions. In this behavioral model, delta agonists show anti-allodynic and anti-hyperalgesic properties [17] — [19] and delta receptor knockout mice display enhanced pain [28]. A Time line of the experiments is shown on top. Test 2: animals re-challenged four hours later with the same drug B and D or the other drug C. Dashed lines represent baseline mechanical or thermal responses pre-CFA.

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To determine if the acute behavioral desensitization after SNC80 treatment could be generalized to other delta agonists, we performed a cross-over experiment Figure 2C. As seen previously, a subsequent injection of SNC80 was ineffective, but repeated injection of ARM continued to attenuate mechanical allodynia and thermal hyperalgesia Figure 2D , Test 2. Altogether, SNC80 treatment prevents further responding to either agonist, whereas ARM treatment does not disrupt subsequent responses to the two drugs.

Therefore, initial exposure to the high-internalizing but not the low-internalizing agonist abolishes DOR function in vivo.

Opioid pharmacology part 2 - mu,kappa and delta receptors

Three other groups of animals were treated identically to control, SNC80 and ARM groups, but were sacrificed for ex vivo analysis, instead of receiving the second drug treatment see time line in Figure 2. In the first group of animals we examined DOR-eGFP subcellular localization in three CNS regions striatum, hippocampus, and spinal cord as well as in dorsal root ganglia using confocal microscopy Figure 3A. Even almost 5 hours after drug administration, very little DOR-eGFP was observed on the cell surface of neurons, in both cell bodies and processes.

Hence, although both agonists showed similar pain relieving properties, only SNC80 produced DOR-eGFP internalization in vivo in both central and peripheral nervous systems. A CNS regions and dorsal root ganglia were analyzed by confocal microscopy and representative images are shown. In the second group of animals, we investigated DOR-eGFP coupling to G proteins in brain membranes and spinal cord homogenates at the time of the second injection Figure 3B.

Only SNC80 treatment produced significantly higher levels of phosphorylated receptor as compared to controls. This result indicates that regulatory processes, which occur at the neuronal level, are triggered by SNC80 only and are likely associated in vivo. We finally determined whether SNCinduced behavioral desensitization could be reversed over time Figure 4A. As seen previously, first exposure to SNC80 significantly attenuated allodynia, and a subsequent injection 4 hours later was ineffective. A delta-opioid receptor lacking the third cytoplasmic loop is generated by atypical mRNA processing in human malignomas.

FEBS Lett. Whistler, J. Modulation of postendocytic sorting of G protein-coupled receptors. Xu, K. Zhang, H. NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.

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Gene Ontology. NCBI Gene. GWAS Catalog. GWAS Central. MGI Mouse Gene. Looking For More References? Crystal Structure Granier et al. Creation Date:. Victor A. Edit History:. Gene Structure. Gene Function. Molecular Genetics. Biochemical Features. An issue that can be particularly difficult to solve is medication overuse headache, Dr. Researchers have also found that SNC80 can alleviate the hypersensitivity normally associated with the chronic administration of the headache medication sumatriptan in animal models, a sign that it could help alleviate medication overuse headache, not just migraine, Dr.

In still another finding, animal models with severe pain following chronic administration of morphine had that pain reduced significantly when SNC80 was given, she said. Researchers are also delving into the potential mechanism through which the delta opioid receptor might regulate headache — specifically assessing the receptors' effects on calcitonin gene related peptide CGRP , which is thought to be an endogenous generator of migraine. In animal models, chronic nitroglycerin, when administered by itself, increases the amount of CGRP in the trigeminal ganglia.

Asked about long-term safety, Dr. Pradhan said there is only one concern that's come to light, and that it is a manageable one.

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Targeting delta opioid receptor may reduce pain without causing addiction

And there are multiple ways in which that adverse side effect can be avoided through proper drug design. Kaye said.


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