scholarly journals Molecular Mechanisms of Opioid Receptor-dependent Signaling and Behavior

2011 ◽  
Vol 115 (6) ◽  
pp. 1363-1381 ◽  
Author(s):  
Ream Al-Hasani ◽  
Michael R. Bruchas
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Molecular Mechanisms ◽  
Human Genetics ◽  
Receptor Subtypes ◽  
Receptor Signaling ◽  
Molecular Pharmacology ◽  
And Behavior ◽  
G Protein Coupled

Opioid receptors have been targeted for the treatment of pain and related disorders for thousands of years and remain the most widely used analgesics in the clinic. Mu (μ), kappa (κ), and delta (δ) opioid receptors represent the originally classified receptor subtypes, with opioid receptor like-1 (ORL1) being the least characterized. All four receptors are G-protein coupled and activate inhibitory G proteins. These receptors form homo- and heterodimeric complexes and signal to kinase cascades and scaffold a variety of proteins.The authors discuss classic mechanisms and developments in understanding opioid tolerance and opioid receptor signaling and highlight advances in opioid molecular pharmacology, behavioral pharmacology, and human genetics. The authors put into context how opioid receptor signaling leads to the modulation of behavior with the potential for therapeutic intervention. Finally, the authors conclude there is a continued need for more translational work on opioid receptors in vivo.

scholarly journals 6,5-Fused Ring, C2-Salvinorin Ester, Dual Kappa and Mu Opioid Receptor Agonists as Analgesics Devoid of Anxiogenic Effects

2021 ◽  
Author(s):  
Nicholas S. Akins ◽  
Nisha Mishra ◽  
Hannah M. Harris ◽  
Narendar Dudhipala ◽  
Seong Jong Kim ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Analgesic Activity ◽  
Mu Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Mu Opioid ◽  
Receptor Agonists ◽  
Opioid Receptor Agonists

Analgesia is commonly mediated through the mu or kappa opioid receptor agonism. Unfortunately, selective mu or kappa receptor agonists often cause harmful side effects. Recently, ligands exhibiting dual agonism to the opioid receptors, such as to mu and kappa, or to mu and delta, have been suggested to temper undesirable adverse effects while retaining analgesic activity. Herein we report an introduction of various 6,5-fused rings to C2 of the salvinorin scaffold <i>via</i> an ester linker. <i>In vitro</i> studies showed that some of these compounds have dual agonism on kappa and mu opioid receptors, while some have triple agonism on kappa, mu, and delta. <i>In vivo </i>studies on the lead dual kappa and mu opioid receptor agonist, compound <b>10</b>, showed that it<b> </b>produced analgesic activity while avoiding anxiogenic effects in murine models, thus providing further strong evidence for the therapeutic advantages of dual opioid receptor agonists over selective opioid receptor agonists.

scholarly journals Estrogen Receptor Signaling and Its Relationship to Cytokines in Systemic Lupus Erythematosus

2010 ◽  
Vol 2010 ◽  
pp. 1-14 ◽  
Author(s):  
E. Kassi ◽  
P. Moutsatsou
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Estrogen Receptor ◽  
Lupus Erythematosus ◽  
Molecular Mechanisms ◽  
Cytokine Production ◽  
Receptor Protein ◽  
Receptor Subtypes ◽  
Receptor Signaling ◽  
Systemic Lupus ◽  
Estrogen Receptor Signaling

Dysregulation of cytokines is among the main abnormalities in Systemic Lupus Erythematosus (SLE). However, although, estrogens, which are known to be involved in lupus disease, influence cytokine production, the underlying molecular mechanisms remain poorly defined. Recent evidence demonstrates the presence of estrogen receptor in various cell types of the immune system, while divergent effects of estrogens on the cytokine regulation are thought to be implicated. In this paper, we provide an overview of the current knowledge as to how estrogen-induced modulation of cytokine production in SLE is mediated by the estrogen receptor while simultaneously clarifying various aspects of estrogen receptor signaling in this disease. The estrogen receptor subtypes, their structure, and the mode of action of estrogens by gene activation and via extranuclear effects are briefly presented. Results regarding the possible correlation between estrogen receptor gene polymorphisms and quantitative changes in the receptor protein to SLE pathology and cytokine production are reviewed.

Opioid Receptors: Cellular and Molecular Mechanisms Underlying Opioid Receptor Function

2012 ◽  
pp. 1304-1312
Author(s):  
Lisa Stowers ◽  
Sandeepa Dey ◽  
Vladana Vukojević ◽  
Yu Ming ◽  
Lars Terenius
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Molecular Mechanisms ◽  
Receptor Function

Selective interactions of spinophilin with the C-terminal domains of the δ- and μ-opioid receptors and G proteins differentially modulate opioid receptor signaling

2012 ◽  
Vol 24 (12) ◽  
pp. 2315-2328 ◽  
Author(s):  
Danai-Dionysia Fourla ◽  
Maria-Pagona Papakonstantinou ◽  
Stavroula-Maria Vrana ◽  
Zafiroula Georgoussi
Keyword(s):  
G Proteins ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Receptor Signaling ◽  
Μ Opioid Receptors ◽  
Selective Interactions ◽  
Terminal Domains

scholarly journals Homo- and hetero-oligomeric interactions between G-protein-coupled receptors in living cells monitored by two variants of bioluminescence resonance energy transfer (BRET): hetero-oligomers between receptor subtypes form more efficiently than between less closely related sequences

2002 ◽  
Vol 365 (2) ◽  
pp. 429-440 ◽  
Author(s):  
Douglas RAMSAY ◽  
Elaine KELLETT ◽  
Mary McVEY ◽  
Stephen REES ◽  
Graeme MILLIGAN
Keyword(s):  
Opioid Receptor ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Living Cells ◽  
G Protein Coupled Receptors ◽  
Receptor Subtypes ◽  
Bioluminescence Resonance Energy Transfer ◽  
Oligomer Formation ◽  
G Protein Coupled ◽  
Energy Acceptor

Homo- and hetero-oligomerization of G-protein-coupled receptors (GPCRs) were examined in HEK-293 cells using two variants of bioluminescence resonance energy transfer (BRET). BRET2 (a variant of BRET) offers greatly improved separation of the emission spectra of the donor and acceptor moieties compared with traditional BRET. Previously recorded homo-oligomerization of the human δ-opioid receptor was confirmed using BRET2. Homo-oligomerization of the κ-opioid receptor was observed using both BRET techniques. Both homo- and hetero-oligomers, containing both δ- and κ-opioid receptors, were unaffected by the presence of receptor ligands. BRET detection of opioid receptor homo- and hetero-oligomers required expression of 50000–100000 copies of the receptor energy acceptor construct per cell. The effectiveness of δ—κ-opioid receptor hetero-oligomer formation was as great as for homomeric interactions. The capacity of the two opioid receptors to form oligomeric complexes with the β2-adrenoceptor was also assessed. Although such interactions were detected, at least 250000 copies per cell of the energy acceptor were required. Requirement for high levels of receptor expression was equally pronounced in attempts to measure hetero-oligomer formation between the κ-opioid receptor and the thyrotropin-releasing hormone receptor-1. These studies indicate that constitutively formed homo- and hetero-oligomers of opioid receptor subtypes can be detected in living cells containing less than 100000 copies of the receptors. However, although hetero-oligomeric interactions between certain less closely related GPCRs can be detected, they appear to be of lower affinity than homo- or hetero-oligomers containing closely related sequences. Interactions recorded between certain GPCR family members in heterologous expression systems are likely to be artefacts of extreme levels of overexpression.

scholarly journals Molecular cloning of a rat κ opioid receptor reveals sequence similarities to the μ and δ opioid receptors

1993 ◽  
Vol 295 (3) ◽  
pp. 625-628 ◽  
Author(s):  
Y Chen ◽  
A Mestek ◽  
J Liu ◽  
L Yu
Keyword(s):  
Adenylate Cyclase ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Kappa Opioid Receptor ◽  
Kappa Opioid ◽  
Brain Cdna Library ◽  
Inhibitory Coupling ◽  
Receptor Cdna ◽  
G Protein Coupled ◽  
Sequence Similarities

By screening a rat brain cDNA library using a cloned mu opioid receptor cDNA as probe, a clone was identified that is very similar to both the mu and delta opioid receptor sequences. Transient expression of this clone in COS-7 cells showed that it encodes a kappa opioid receptor, designated KOR-1, which is capable of high-affinity binding to kappa-selective ligands. Treatment of transfected cell membranes with bremazocine, a kappa-selective agonist, resulted in a 53% decrease in adenylate cyclase activity, indicating that this kappa opioid receptor displays inhibitory coupling to adenylate cyclase. Thus, one member from each of the three opioid receptor types, mu, kappa and delta, has been molecularly cloned. Analysis of sequence similarities among these opioid receptors, as well as between opioid receptors and other G-protein-coupled receptors, revealed regions of sequence conservation that may underlie the ligand-binding and functional specificities of opioid receptors.

scholarly journals Site Selective C-H Functionalization of Mitragyna Alkaloids Reveals a Molecular Switch for Tuning Opioid Receptor Signaling Efficacy

2020 ◽  
Author(s):  
Srijita Bhowmik ◽  
Juraj Galeta ◽  
Vaclav Havel ◽  
Melissa Nelson ◽  
Abdelfattah Faouzi ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Parent Compound ◽  
Fine Tuning ◽  
Receptor Signaling ◽  
Self Medication ◽  
Pain Syndromes ◽  
Opioid Medications ◽  
Site Selective

<p>Mitragynine is the most abundant alkaloid component of the psychoactive plant material “kratom”, which according to numerous anecdotal reports shows efficacy in self-medication for pain syndromes, depression, anxiety, and substance use disorders. We developed a new synthetic method for selective functionalization of the unexplored C11 position of the mitragynine scaffold (C6 position in indole numbering) via the use of an indole-ethylene glycol adduct and subsequent iridium-catalyzed borylation. We discovered that C11 represents a key locant for fine-tuning opioid receptor signaling efficacy. In the 7-hydroxymitragynine (7OH) series, the high efficacy parent compound was transformed to an equipotent low efficacy agonist by introducing a fluorine substituent in this position (11-F-7OH), as demonstrated in vitro at both mouse and human mu opioid receptors (mMOR/hMOR) and in vivo in mouse analgesia tests after systemic administration. Low efficacy opioid agonists are of high interest as candidates for generating safer opioid medications with mitigated adverse effects.</p>

scholarly journals IL-10 Receptor Signaling Empowers Regulatory T Cells to Control Th17 Responses and Protect from GN

2018 ◽  
Vol 29 (7) ◽  
pp. 1825-1837 ◽  
Author(s):  
Paul Diefenhardt ◽  
Anna Nosko ◽  
Malte A. Kluger ◽  
Johannes V. Richter ◽  
Claudia Wegscheid ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Th17 Cells ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Receptor Signaling ◽  
Dendritic Cell Activation ◽  
Fluorescent Reporter

Background Th17 cells are central pathogenic mediators of autoimmune disease, including many forms of GN. IL-10 receptor signaling (IL-10R) in regulatory T cells (Tregs) has been implicated in the downregulation of Th17 cells, but the underlying molecular mechanisms and functional relevance of this process remain unclear.Methods We generated mice with Treg-specific IL-10Ra deficiency and subjected these mice to nephrotoxic serum–induced nephritis as a model of crescentic GN. Immune responses and Treg phenotypes were extensively analyzed.Results Compared with controls, mice with IL-10Ra−/− Tregs showed a spontaneously overshooting Th17 immune response. This hyper-Th17 phenotype was further boosted during GN and associated with aggravated renal injury. Notably, abrogation of IL-10Ra signaling in Tregs increased dendritic cell activation and production of Th17-inducing cytokines. In contrast, Treg trafficking and expression of chemokine receptor CCR6 remained unaffected, indicating mechanisms of Th17 control, differing from those of previously identified CCR6+ Treg17 cells. Indeed, the capacity for direct in vitro suppression of Th17 responses by IL-10Ra−/− Tregs was significantly impaired. As underlying pathology, analyses conducted in vitro and in vivo using double-fluorescent reporter mice revealed strikingly decreased IL-10 production by IL-10Ra−/− Tregs. To assess, whether reduced IL-10 could explain the hyper Th17 phenotype, competitive cotransfer experiments were performed. Supporting our concept, IL-10Ra−/− T cells differentiated into Th17 cells at much higher frequencies than wild type T cells did during GN.Conclusions IL-10R engagement optimizes Treg-mediated suppression of Th17 immunity. We hypothesize a feed-forward loop, in which IL-10Ra signaling reinforces IL-10 secretion by Tregs which potently controls Th17 development via direct and indirect mechanisms. IL-10R thus may be a promising therapeutic target for the treatment of GN.

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