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Neuropsychopharmacology : Official... Dec 2018Mu opioid receptor agonists are among the most powerful analgesic medications but also among the most addictive. The current opioid crisis has energized a quest to... (Review)
Review
Mu opioid receptor agonists are among the most powerful analgesic medications but also among the most addictive. The current opioid crisis has energized a quest to develop opioid analgesics that are devoid of untoward effects. Since their discovery in the 1970's, there have been major advances in our understanding of the endogenous opioid systems that these drugs target. Yet many questions remain and the development of non-addictive opioid analgesics has not been achieved. However, access to new molecular, genetic and computational tools have begun to elucidate the structural dynamics of opioid receptors, the scaffolding that links them to intracellular signaling cascades, their cellular trafficking and the distinct ways that various opioid drugs modify them. This mini-review highlights some of the chemical and pharmacological findings and new perspectives that have arisen from studies using these tools. They reveal multiple layers of complexity of opioid receptor function, including a spatiotemporal specificity in opioid receptor-induced cellular signaling, ligand-directed biased signaling, allosteric modulation of ligand interactions, heterodimerization of different opioid receptors, and the existence of slice variants with different ligand specificity. By untangling these layers, basic research into the chemistry and pharmacology of opioid receptors is guiding the way towards deciphering the mysteries of tolerance and physical dependence that have plagued the field and is providing a platform for the development of more effective and safer opioids.
Topics: Affect; Allosteric Regulation; Analgesics, Opioid; Animals; Brain; Humans; Pain; Receptors, Opioid; Signal Transduction
PubMed: 30250308
DOI: 10.1038/s41386-018-0225-3 -
Journal of Pharmacological and... 2022Opioid receptors are divided into the three classical types: MOP(μ:mu), DOP(δ:delta) and KOP(κ:kappa) that are naloxone-sensitive and an additional... (Review)
Review
Opioid receptors are divided into the three classical types: MOP(μ:mu), DOP(δ:delta) and KOP(κ:kappa) that are naloxone-sensitive and an additional naloxone-insensitive nociceptin/orphanin FQ(N/OFQ) peptide receptor(NOP). Studies to determine opioid receptor location and turnover variably rely on; (i) measuring receptor mRNA, (ii) genetically tagging receptors, (iii) labelling receptors with radioligands, (iv) use of antibodies in immunohistochemistry/Western Blotting or (v) measuring receptor function coupled with the use of selective antagonists. All have their drawbacks with significant issues relating to mRNA not necessarily predicting protein, poor antibody selectivity and utility of radiolabels in low expression systems. In this minireview we discuss use of fluorescently labelled opioid receptor ligands. To maintain the pharmacological properties of the corresponding parent ligand fluorescently labelled ligands must take into account fluorophore (brightness and propensity to bleach), linker length and chemistry, and site to which the linker (and hence probe) will be attached. Use of donor and acceptor fluorophores with spectral overlap facilitates use in FRET type assays to determine proximity of ligand or tagged receptor pairs. There is a wide range of probes of agonist and antagonist nature for all four opioid receptor types; caution is needed with agonist probes due to the possibility for internalization. We have produced two novel ATTO based probes; Dermorphin (MOP) and N/OFQ (NOP). These probes label MOP and NOP in a range of preparations and using N/OFQ we demonstrate internalization and ligand-receptor interaction by FRET. Fluorescent opioid probes offer potential methodological advantages over more traditional use of antibodies and radiolabels.
Topics: Analgesics, Opioid; Fluorescent Dyes; Ligands; Receptors, Opioid; Receptors, Opioid, mu
PubMed: 34728348
DOI: 10.1016/j.vascn.2021.107132 -
Current Opinion in Pharmacology Feb 2010Homomerization and heteromerization of 7 transmembrane spanning (7TM)/G-protein-coupled receptors (GPCRs) have been an important field of study. Whereas initial studies... (Review)
Review
Homomerization and heteromerization of 7 transmembrane spanning (7TM)/G-protein-coupled receptors (GPCRs) have been an important field of study. Whereas initial studies were performed in artificial cell systems, recent publications are shifting the focus to the in vivo relevance of heteromerization. This is especially apparent for the field of opioid receptors. Drugs have been identified that selectively target opioid heteromers of the delta-opioid receptor with the kappa and the mu-opioid receptors that influence nociception and ethanol consumption, respectively. In addition, in several cases, the specific physiological response produced by the heteromer may be directly attributed to a difference in receptor trafficking properties of the heteromers compared with their homomeric counterparts. This review attempts to highlight some of the latest developments with regard to opioid receptor heteromer trafficking and pharmacology.
Topics: Alcohol Drinking; Animals; Drug Delivery Systems; Humans; Ligands; Protein Binding; Protein Multimerization; Protein Transport; Receptors, Opioid
PubMed: 19846340
DOI: 10.1016/j.coph.2009.09.007 -
European Journal of Pharmacology Sep 2015Opioid receptors are important drug targets for pain management, addiction, and mood disorders. Although substantial research on these important subtypes of G... (Review)
Review
Opioid receptors are important drug targets for pain management, addiction, and mood disorders. Although substantial research on these important subtypes of G protein-coupled receptors has been conducted over the past two decades to discover ligands with higher specificity and diminished side effects, currently used opioid therapeutics remain suboptimal. Luckily, recent advances in structural biology of opioid receptors provide unprecedented insights into opioid receptor pharmacology and signaling. We review here a few recent studies that have used the crystal structures of opioid receptors as a basis for revealing mechanistic details of signal transduction mediated by these receptors, and for the purpose of drug discovery.
Topics: Animals; Drug Design; Humans; Ligands; Pharmacology; Protein Multimerization; Receptors, Opioid; Signal Transduction
PubMed: 25981301
DOI: 10.1016/j.ejphar.2015.05.012 -
Nature Reviews. Drug Discovery Mar 2023
Topics: Humans; Receptors, Opioid; Receptors, Opioid, mu; Analgesics, Opioid
PubMed: 36755159
DOI: 10.1038/d41573-023-00022-y -
Clinical and Experimental Pharmacology... Jul 19991. Three pharmacological types of opioid receptors, mu, delta and kappa, and their corresponding genes have been identified. Although other types of opioid receptors... (Review)
Review
1. Three pharmacological types of opioid receptors, mu, delta and kappa, and their corresponding genes have been identified. Although other types of opioid receptors have been suggested, their existence has not been established unequivocally. A fourth opioid receptor, ORL1, which is genetically closely related to the others, has also been isolated. ORL1 responds to the endogenous agonist nociceptin (orphanin FQ) and displays a pharmacological profile that differs greatly from mu, delta and kappa receptors. 2. All opioid receptors mediate many of their cellular effects via activation of heterotrimeric G-proteins. The mu, delta and kappa receptors are all capable of interacting with the pertussis toxin-sensitive G-protein alpha-subunits Gi1, Gi2, Gi3, Go1, Go2 and the pertussis toxin-insensitive Gz and G16. None of the opioid receptors interacts substantially with Gs and mu receptors do not activate Gq, G11, G12, G13, or G14. 3. Differential coupling of different opioid receptors to most types of G-proteins is marginal. The mu, delta and kappa receptors appear to preferentially activate Go and Gi2 over other pertussis toxin-sensitive G-proteins, although there is evidence that mu receptors show some preference for Gi3. delta Receptors couple more efficiently to G16 than do mu or kappa receptors. 4. There is some evidence that opioid receptors, particularly mu and ORL1 receptors, can also couple to cellular effectors in a G-protein-independent manner. 5. In general, the consequences of activation of any of the opioid receptors in a given cell type depend more on the profile (stoichiometry) of the G-proteins and effectors expressed than on the type of opioid receptor present in the cell. Notions that different types of opioid receptors intrinsically couple preferentially to one type of effector rather than another should, therefore, be discarded.
Topics: Animals; GTP-Binding Proteins; Humans; Neurons; Receptors, Opioid
PubMed: 10405772
DOI: 10.1046/j.1440-1681.1999.03049.x -
Neuroscience Dec 2016In recent years, the delta opioid receptor has attracted increasing interest as a target for the treatment of chronic pain and emotional disorders. Due to their... (Review)
Review
In recent years, the delta opioid receptor has attracted increasing interest as a target for the treatment of chronic pain and emotional disorders. Due to their therapeutic potential, numerous tools have been developed to study the delta opioid receptor from both a molecular and a functional perspective. This review summarizes the most commonly available tools, with an emphasis on their use and limitations. Here, we describe (1) the cell-based assays used to study the delta opioid receptor. (2) The features of several delta opioid receptor ligands, including peptide and non-peptide drugs. (3) The existing approaches to detect delta opioid receptors in fixed tissue, and debates that surround these techniques. (4) Behavioral assays used to study the in vivo effects of delta opioid receptor agonists; including locomotor stimulation and convulsions that are induced by some ligands, but not others. (5) The characterization of genetically modified mice used specifically to study the delta opioid receptor. Overall, this review aims to provide a guideline for the use of these tools with the final goal of increasing our understanding of delta opioid receptor physiology.
Topics: Animals; Cell Line; Humans; Mice, Transgenic; Receptors, Opioid, delta; Research Design
PubMed: 27349452
DOI: 10.1016/j.neuroscience.2016.06.028 -
Biological Psychiatry Jun 2023(S)-ketamine is an NMDA receptor antagonist, but it also binds to and activates mu opioid receptors (MORs) and kappa opioid receptors in vitro. However, the extent to...
BACKGROUND
(S)-ketamine is an NMDA receptor antagonist, but it also binds to and activates mu opioid receptors (MORs) and kappa opioid receptors in vitro. However, the extent to which these receptors contribute to (S)-ketamine's in vivo pharmacology is unknown.
METHODS
We investigated the extent to which (S)-ketamine interacts with opioid receptors in rats by combining in vitro and in vivo pharmacological approaches, in vivo molecular and functional imaging, and behavioral procedures relevant to human abuse liability.
RESULTS
We found that the preferential opioid receptor antagonist naltrexone decreased (S)-ketamine self-administration and (S)-ketamine-induced activation of the nucleus accumbens, a key brain reward region. A single reinforcing dose of (S)-ketamine occupied brain MORs in vivo, and repeated doses decreased MOR density and activity and decreased heroin reinforcement without producing changes in NMDA receptor or kappa opioid receptor density.
CONCLUSIONS
These results suggest that (S)-ketamine's abuse liability in humans is mediated in part by brain MORs.
Topics: Rats; Humans; Animals; Ketamine; Receptors, Opioid, mu; Receptors, N-Methyl-D-Aspartate; Heroin; Receptors, Opioid; Receptors, Opioid, kappa
PubMed: 36841701
DOI: 10.1016/j.biopsych.2022.12.019 -
British Journal of Pharmacology Jan 2015Recent developments in the study of the structure and function of opioid receptors raise significant challenges for the definition of individual receptor types and the... (Review)
Review
UNLABELLED
Recent developments in the study of the structure and function of opioid receptors raise significant challenges for the definition of individual receptor types and the development of a nomenclature that precisely describes isoforms that may subserve different functions in vivo. Presentations at the 2013 meeting of the International Narcotics Research Conference in Cairns, Australia, considered some of the new discoveries that are now unravelling the complexities of opioid receptor signalling. Variable processing of opioid receptor messenger RNAs may lead to the presence of several isoforms of the μ receptor. Each opioid receptor type can function either as a monomer or as part of a homo- or heterodimer or higher multimer. Additionally, recent evidence points to the existence of agonist bias in the signal transduction pathways activated through μ receptors, and to the presence of regulatory allosteric sites on the receptors. This brief review summarizes the recent discoveries that raise challenges for receptor definition and the characterization of signal transduction pathways activated by specific receptor forms.
LINKED ARTICLES
This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.
Topics: Animals; Humans; Protein Isoforms; Receptors, Opioid; Terminology as Topic
PubMed: 24528283
DOI: 10.1111/bph.12612 -
Current Pharmaceutical Design 2013Tritiated opioid ligands are essential tools for the identification of opioid receptors. This review deals with the syntheses of tritiated opioid peptide derivatives,... (Review)
Review
Tritiated opioid ligands are essential tools for the identification of opioid receptors. This review deals with the syntheses of tritiated opioid peptide derivatives, including enkephalins, dynorphins, dermorphins, deltorphins and endomorphins, and also discusses tritium-labeled nonpeptide opioids. It additionally focuses on the relevance of tritium-labeled opioid compounds as research tools for investigating opioid receptor pharmacology. Agonists and antagonists are used for the characterization of new opioid ligands by means of radioreceptor binding assays. Further topics covered in this review are the distribution of the endogenous peptides in the central nervous system and peripheral tissues, and degradation studies of opioids in brain membrane preparations and the blood.
Topics: Ligands; Radioligand Assay; Receptors, Opioid
PubMed: 23448471
DOI: 10.2174/138161281942140105170259