Grks As Key Modulators of Opioid Receptor Function
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Janet Robishaw, PhD Senior Associate Dean for Research Chair and Professor, Biomedical Science Florida Atlantic University Charles E. Schmidt College of Medicine Disclosures and Conflicts • I have no actual or potential conflict of interest in relation to this program/presentation. • Research support: Robishaw, MPI Robishaw, MPI R01 DA044015 R01 HL134015 Genetic Predictors of Opioid Addiction Genetic Heterogeneity of Sleep Apnea 2017-2022 2016-2021 Robishaw, PI Robishaw, MPI R01 GM114665 R01 GM111913 Novel Aspects of Golf Signaling GPCR Variants in Complex Diseases 2015-2019 2015-2019 Learning Objectives 1. Review the scope and root cause of opioid use disorder 2. Discuss the effects of opioid medications on the brain and body 3. Stress the importance of clinical judgement and discovery to address the opioid crisis 4. Highlight the clinical implications between opioid use disorder and heroin abuse Two Endemic Problems Chronic Pain Opioid Use Disorder Debilitating disorder Chronic, relapsing disorder 100 million Americans 2 million Americans Costs $630 billion dollars per year Costs $80 billion per year #1 presenting complaint to doctors # 1 cause of accidental death #1 reason for lost productivity #1 driver of heroin epidemic #1 treatment –opioid medications ? treatment Pain Relief and “Addiction” Share A Common Mechanism of Action m-Opioid Receptor Brain Regions Involved in Pleasure and Reward Increase dopamine release Brain Regions Involved in Pain Perception Brainstem Involved in Respiratory Control Spinal Cord Involved in Pain Transmission Prevent ascending transmission Turn on descending inhibitory systems These receptors are dispersed Inhibit peripheral nocioceptors throughout the body, thereby accounting for their differential Body effects on pain and reward paths. -
Biased Versus Partial Agonism in the Search for Safer Opioid Analgesics
molecules Review Biased versus Partial Agonism in the Search for Safer Opioid Analgesics Joaquim Azevedo Neto 1 , Anna Costanzini 2 , Roberto De Giorgio 2 , David G. Lambert 3 , Chiara Ruzza 1,4,* and Girolamo Calò 1 1 Department of Biomedical and Specialty Surgical Sciences, Section of Pharmacology, University of Ferrara, 44121 Ferrara, Italy; [email protected] (J.A.N.); [email protected] (G.C.) 2 Department of Morphology, Surgery, Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy; [email protected] (A.C.); [email protected] (R.D.G.) 3 Department of Cardiovascular Sciences, Anesthesia, Critical Care and Pain Management, University of Leicester, Leicester LE1 7RH, UK; [email protected] 4 Technopole of Ferrara, LTTA Laboratory for Advanced Therapies, 44122 Ferrara, Italy * Correspondence: [email protected] Academic Editor: Helmut Schmidhammer Received: 23 July 2020; Accepted: 23 August 2020; Published: 25 August 2020 Abstract: Opioids such as morphine—acting at the mu opioid receptor—are the mainstay for treatment of moderate to severe pain and have good efficacy in these indications. However, these drugs produce a plethora of unwanted adverse effects including respiratory depression, constipation, immune suppression and with prolonged treatment, tolerance, dependence and abuse liability. Studies in β-arrestin 2 gene knockout (βarr2( / )) animals indicate that morphine analgesia is potentiated − − while side effects are reduced, suggesting that drugs biased away from arrestin may manifest with a reduced-side-effect profile. However, there is controversy in this area with improvement of morphine-induced constipation and reduced respiratory effects in βarr2( / ) mice. Moreover, − − studies performed with mice genetically engineered with G-protein-biased mu receptors suggested increased sensitivity of these animals to both analgesic actions and side effects of opioid drugs. -
The in Vitro Binding Properties of Non-Peptide AT1 Receptor Antagonists
Journal of Clinical and Basic Cardiology An Independent International Scientific Journal Journal of Clinical and Basic Cardiology 2002; 5 (1), 75-82 The In Vitro Binding Properties of Non-Peptide AT1 Receptor Antagonists Vanderheyden PML, Fierens FLP, Vauquelin G, Verheijen I Homepage: www.kup.at/jcbc Online Data Base Search for Authors and Keywords Indexed in Chemical Abstracts EMBASE/Excerpta Medica Krause & Pachernegg GmbH · VERLAG für MEDIZIN und WIRTSCHAFT · A-3003 Gablitz/Austria REVIEWS Binding of Non-Peptide AT1 Receptor Antagonists J Clin Basic Cardiol 2002; 5: 75 The In Vitro Binding Properties of Non-Peptide AT1 Receptor Antagonists P. M. L. Vanderheyden, I. Verheijen, F. L. P. Fierens, G. Vauquelin A major breakthrough in the development of AT1 receptor antagonists as promising antihypertensive drugs, was the synthe- sis of potent and selective non-peptide antagonists for this receptor. In the present manuscript an overview of the in vitro binding properties of these antagonists is discussed. In particular, CHO cells expressing human AT1 receptors offer a well- defined and efficient experimental system, in which antagonist binding and inhibition of angiotensin II induced responses could be measured. From these studies it appeared that all investigated antagonists were competitive with respect to angiotensin II and bind to a common or overlapping binding site on the receptor. Moreover this model allowed us to describe the mecha- nism by which certain antagonists depress the maximal angiotensin II responsiveness in vascular contraction studies. Insur- mountable inhibition was found to be related to the dissociation rate of the antagonist-AT1 receptor complex. The almost complete (candesartan), partially insurmountable inhibition (irbesartan, EXP3174, valsartan) or surmountable inhibition (losartan), was explained by the ability of the antagonist-receptor complex to adopt a fast and slow reversible state. -
Atrazine and Cell Death Symbol Synonym(S)
Supplementary Table S1: Atrazine and Cell Death Symbol Synonym(s) Entrez Gene Name Location Family AR AIS, Andr, androgen receptor androgen receptor Nucleus ligand- dependent nuclear receptor atrazine 1,3,5-triazine-2,4-diamine Other chemical toxicant beta-estradiol (8R,9S,13S,14S,17S)-13-methyl- Other chemical - 6,7,8,9,11,12,14,15,16,17- endogenous decahydrocyclopenta[a]phenanthrene- mammalian 3,17-diol CGB (includes beta HCG5, CGB3, CGB5, CGB7, chorionic gonadotropin, beta Extracellular other others) CGB8, chorionic gonadotropin polypeptide Space CLEC11A AW457320, C-type lectin domain C-type lectin domain family 11, Extracellular growth factor family 11, member A, STEM CELL member A Space GROWTH FACTOR CYP11A1 CHOLESTEROL SIDE-CHAIN cytochrome P450, family 11, Cytoplasm enzyme CLEAVAGE ENZYME subfamily A, polypeptide 1 CYP19A1 Ar, ArKO, ARO, ARO1, Aromatase cytochrome P450, family 19, Cytoplasm enzyme subfamily A, polypeptide 1 ESR1 AA420328, Alpha estrogen receptor,(α) estrogen receptor 1 Nucleus ligand- dependent nuclear receptor estrogen C18 steroids, oestrogen Other chemical drug estrogen receptor ER, ESR, ESR1/2, esr1/esr2 Nucleus group estrone (8R,9S,13S,14S)-3-hydroxy-13-methyl- Other chemical - 7,8,9,11,12,14,15,16-octahydro-6H- endogenous cyclopenta[a]phenanthren-17-one mammalian G6PD BOS 25472, G28A, G6PD1, G6PDX, glucose-6-phosphate Cytoplasm enzyme Glucose-6-P Dehydrogenase dehydrogenase GATA4 ASD2, GATA binding protein 4, GATA binding protein 4 Nucleus transcription TACHD, TOF, VSD1 regulator GHRHR growth hormone releasing -
Pain Therapy E Are There New Options on the Horizon?
Best Practice & Research Clinical Rheumatology 33 (2019) 101420 Contents lists available at ScienceDirect Best Practice & Research Clinical Rheumatology journal homepage: www.elsevierhealth.com/berh 4 Pain therapy e Are there new options on the horizon? * Christoph Stein a, , Andreas Kopf b a Department of Experimental Anesthesiology, Charite Campus Benjamin Franklin, D-12200 Berlin, Germany b Department of Anesthesiology and Intensive Care Medicine, Charite Campus Benjamin Franklin, D-12200 Berlin, Germany abstract Keywords: Opioid crisis This article reviews the role of analgesic drugs with a particular Chronic noncancer pain emphasis on opioids. Opioids are the oldest and most potent drugs Chronic nonmalignant pain for the treatment of severe pain, but they are burdened by detri- Opioid mental side effects such as respiratory depression, addiction, Opiate sedation, nausea, and constipation. Their clinical application is Inflammation undisputed in acute (e.g., perioperative) and cancer pain, but their Opioid receptor long-term use in chronic pain has met increasing scrutiny and has Misuse Abuse contributed to the current opioid crisis. We discuss epidemiolog- Bio-psycho-social ical data, pharmacological principles, clinical applications, and research strategies aiming at novel opioids with reduced side effects. © 2019 Elsevier Ltd. All rights reserved. The opioid epidemic The treatment of pain remains a huge challenge in clinical medicine and public health [1,2]. Pain is the major symptom in rheumatoid (RA) and osteoarthritis (OA) [3,4]. Both are chronic conditions that are not linked to malignant disease, and pain can occur even in the absence of inflammatory signs (see chapter “Pain without inflammation”). Unfortunately, there is a lack of fundamental knowledge about the management of chronic noncancer pain. -
Opioid Receptorsreceptors
OPIOIDOPIOID RECEPTORSRECEPTORS defined or “classical” types of opioid receptor µ,dk and . Alistair Corbett, Sandy McKnight and Graeme Genes encoding for these receptors have been cloned.5, Henderson 6,7,8 More recently, cDNA encoding an “orphan” receptor Dr Alistair Corbett is Lecturer in the School of was identified which has a high degree of homology to Biological and Biomedical Sciences, Glasgow the “classical” opioid receptors; on structural grounds Caledonian University, Cowcaddens Road, this receptor is an opioid receptor and has been named Glasgow G4 0BA, UK. ORL (opioid receptor-like).9 As would be predicted from 1 Dr Sandy McKnight is Associate Director, Parke- their known abilities to couple through pertussis toxin- Davis Neuroscience Research Centre, sensitive G-proteins, all of the cloned opioid receptors Cambridge University Forvie Site, Robinson possess the same general structure of an extracellular Way, Cambridge CB2 2QB, UK. N-terminal region, seven transmembrane domains and Professor Graeme Henderson is Professor of intracellular C-terminal tail structure. There is Pharmacology and Head of Department, pharmacological evidence for subtypes of each Department of Pharmacology, School of Medical receptor and other types of novel, less well- Sciences, University of Bristol, University Walk, characterised opioid receptors,eliz , , , , have also been Bristol BS8 1TD, UK. postulated. Thes -receptor, however, is no longer regarded as an opioid receptor. Introduction Receptor Subtypes Preparations of the opium poppy papaver somniferum m-Receptor subtypes have been used for many hundreds of years to relieve The MOR-1 gene, encoding for one form of them - pain. In 1803, Sertürner isolated a crystalline sample of receptor, shows approximately 50-70% homology to the main constituent alkaloid, morphine, which was later shown to be almost entirely responsible for the the genes encoding for thedk -(DOR-1), -(KOR-1) and orphan (ORL ) receptors. -
Constitutive Activation of G Protein-Coupled Receptors and Diseases: Insights Into Mechanisms of Activation and Therapeutics
Pharmacology & Therapeutics 120 (2008) 129–148 Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Associate editor: S. Enna Constitutive activation of G protein-coupled receptors and diseases: Insights into mechanisms of activation and therapeutics Ya-Xiong Tao ⁎ Department of Anatomy, Physiology and Pharmacology, 212 Greene Hall, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA article info abstract The existence of constitutive activity for G protein-coupled receptors (GPCRs) was first described in 1980s. In Keywords: 1991, the first naturally occurring constitutively active mutations in GPCRs that cause diseases were reported G protein-coupled receptor Disease in rhodopsin. Since then, numerous constitutively active mutations that cause human diseases were reported Constitutively active mutation in several additional receptors. More recently, loss of constitutive activity was postulated to also cause Inverse agonist diseases. Animal models expressing some of these mutants confirmed the roles of these mutations in the Mechanism of activation pathogenesis of the diseases. Detailed functional studies of these naturally occurring mutations, combined Transgenic model with homology modeling using rhodopsin crystal structure as the template, lead to important insights into the mechanism of activation in the absence of crystal structure of GPCRs in active state. Search for inverse Abbreviations: agonists on these receptors will be critical for correcting the diseases cause by activating mutations in GPCRs. ADRP, autosomal dominant retinitis pigmentosa Theoretically, these inverse agonists are better therapeutics than neutral antagonists in treating genetic AgRP, Agouti-related protein AR, adrenergic receptor diseases caused by constitutively activating mutations in GPCRs. CAM, constitutively active mutant © 2008 Elsevier Inc. -
Developments in Opioid Drugs
Spotlight on drugs Developments in opioid Advanced courses 2019 analgesics Dr Andrew Wilcock DM FRCP [email protected] 1 2 1 2 Outline of talk • background – cancer pain / strong opioids Background • pharmacology • new approaches (as we go) • summary • discussion/questions. 3 4 Opioids WHO analgesic ladder for cancer pain • central to the management of moderate–severe acute pain and cancer pain. 5 6 1 Broad-spectrum analgesia Opioids: why improve? Ultimate aim to: • improve efficacy • eliminate / reduce risk of undesirable effects, e.g.: – constipation – dependence – respiratory depression – sedation – tolerance. 7 8 Opioids: chemical classification Pharmacology 9 10 Opioid: receptors Four main types: • μ • κ • δ • opioid-receptor-like 1 (OPRL-1) – opioid-related nociceptin receptor 1 – nociceptin opioid peptide (NOP) – nociceptin/orphanin FQ (N/OFQ). 11 12 2 Opioid: receptors Opioids Generally: • μ-opioid receptor clinically most relevant for analgesia and undesirable effects • Centrally: dorsal horn, higher centres – pre-synaptic: inhibit release of neurotransmitters – post-synaptic: hyperpolarize neurone • Peripherally: nerve endings, DRG, (immune cells) – inflammation upregulates opioid receptors 13 14 15 16 New approaches for opioid analgesics 17 18 3 New approaches for opioid analgesics Include: 1. Broad-spectrum 2. Injury-targeted 1. ‘Broad-spectrum’ opioid agonists 3. Biased agonists Not exhaustive list, but main finds when searching the literature. Gunther T et al. (2018); Chan HCS et al. (2017) 19 20 ‘Broad-spectrum’ opioid agonists Differential analgesic and UE of opioid receptors Targeting multiple receptors may have synergistic analgesic effects & lower UE • μ most important analgesia / UE • selective κ and δ agonists – limited analgesia / own UE – κ (e.g. -
Measuring Ligand Efficacy at the Mu- Opioid Receptor Using A
RESEARCH ARTICLE Measuring ligand efficacy at the mu- opioid receptor using a conformational biosensor Kathryn E Livingston1,2, Jacob P Mahoney1,2, Aashish Manglik3, Roger K Sunahara4, John R Traynor1,2* 1Department of Pharmacology, University of Michigan Medical School, Ann Arbor, United States; 2Edward F Domino Research Center, University of Michigan, Ann Arbor, United States; 3Department of Pharmaceutical Chemistry, School of Pharmacy, University of California San Francisco, San Francisco, United States; 4Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, United States Abstract The intrinsic efficacy of orthosteric ligands acting at G-protein-coupled receptors (GPCRs) reflects their ability to stabilize active receptor states (R*) and is a major determinant of their physiological effects. Here, we present a direct way to quantify the efficacy of ligands by measuring the binding of a R*-specific biosensor to purified receptor employing interferometry. As an example, we use the mu-opioid receptor (m-OR), a prototypic class A GPCR, and its active state sensor, nanobody-39 (Nb39). We demonstrate that ligands vary in their ability to recruit Nb39 to m- OR and describe methadone, loperamide, and PZM21 as ligands that support unique R* conformation(s) of m-OR. We further show that positive allosteric modulators of m-OR promote formation of R* in addition to enhancing promotion by orthosteric agonists. Finally, we demonstrate that the technique can be utilized with heterotrimeric G protein. The method is cell- free, signal transduction-independent and is generally applicable to GPCRs. DOI: https://doi.org/10.7554/eLife.32499.001 *For correspondence: [email protected] Competing interests: The authors declare that no Introduction competing interests exist. -
BBC Program 2016.Pages
March 5-6, 2016 La Quinta Inn & Suites Medical Center San Antonio, TX Behavior, Biology, and Chemistry: Translational Research in Addiction BBC 2016 BBC Publications BBC 2011 Stockton Jr SD and Devi LA (2012) Functional relevance of μ–δ opioid receptor heteromerization: A Role in novel signaling and implications for the treatment of addiction disorders: From a symposium on new concepts in mu-opioid pharmacology. Drug and Alcohol Dependence Mar 1;121(3):167-72. doi: 10.1016/j.drugalcdep.2011.10.025. Epub 2011 Nov 23 Traynor J (2012) μ-Opioid receptors and regulators of G protein signaling (RGS) proteins: From a sym- posium on new concepts in mu-opioid pharmacology. Drug and Alcohol Dependence Mar 1;121(3): 173-80. doi: 10.1016/j.drugalcdep.2011.10.027. Epub 2011 Nov 29 Lamb K, Tidgewell K, Simpson DS, Bohn LM and Prisinzano TE (2012) Antinociceptive effects of herkinorin, a MOP receptor agonist derived from salvinorin A in the formalin test in rats: New concepts in mu opioid receptor pharmacology: From a symposium on new concepts in mu-opioid pharma- cology. Drug and Alcohol Dependence Mar 1;121(3):181-8. doi: 10.1016/j.drugalcdep.2011.10.026. Epub 2011 Nov 26 Whistler JL (2012) Examining the role of mu opioid receptor endocytosis in the beneficial and side-ef- fects of prolonged opioid use: From a symposium on new concepts in mu-opioid pharmacology. Drug and Alcohol Dependence Mar 1;121(3):189-204. doi: 10.1016/j.drugalcdep.2011.10.031. Epub 2012 Jan 9 BBC 2012 Zorrilla EP, Heilig M, de Wit, H and Shaham Y (2013) Behavioral, biological, and chemical perspectives on targeting CRF1 receptor antagonists to treat alcoholism. -
In the IUPHAR/BPS Guide to Pharmacology Database
IUPHAR/BPS Guide to Pharmacology CITE https://doi.org/10.2218/gtopdb/F16/2019.4 Class A Orphans (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database Stephen P.H. Alexander1, Jim Battey2, Helen E. Benson3, Richard V. Benya4, Tom I. Bonner5, Anthony P. Davenport6, Satoru Eguchi7, Anthony Harmar3, Nick Holliday1, Robert T. Jensen2, Sadashiva Karnik8, Evi Kostenis9, Wen Chiy Liew3, Amy E. Monaghan3, Chido Mpamhanga10, Richard Neubig11, Adam J. Pawson3, Jean-Philippe Pin12, Joanna L. Sharman3, Michael Spedding13, Eliot Spindel14, Leigh Stoddart15, Laura Storjohann16, Walter G. Thomas17, Kalyan Tirupula8 and Patrick Vanderheyden18 1. University of Nottingham, UK 2. National Institutes of Health, USA 3. University of Edinburgh, UK 4. University of Illinois at Chicago, USA 5. National Institute of Mental Health, USA 6. University of Cambridge, UK 7. Temple University, USA 8. Cleveland Clinic Lerner Research Institute, USA 9. University of Bonn, Germany 10. LifeArc, UK 11. Michigan State University, USA 12. Université de Montpellier, France 13. Spedding Research Solutions SARL, France 14. Oregon Health & Science University, USA 15. University of Glasgow, UK 16. University of Utah, USA 17. University of Queensland, Australia 18. Vrije Universiteit Brussel, Belgium Abstract Table 1 lists a number of putative GPCRs identified by NC-IUPHAR [191], for which preliminary evidence for an endogenous ligand has been published, or for which there exists a potential link to a disease, or disorder. These GPCRs have recently been reviewed in detail [148]. The GPCRs in Table 1 are all Class A, rhodopsin-like GPCRs. Class A orphan GPCRs not listed in Table 1 are putative GPCRs with as-yet unidentified endogenous ligands. -
TRPV1 Is a Physiological Regulator of Μ-Opioid Receptors
TRPV1 is a physiological regulator of μ-opioid receptors Paul C. Scherera,1, Nicholas W. Zaccora,1, Neil M. Neumannb, Chirag Vasavdaa, Roxanne Barrowa, Andrew J. Ewaldb, Feng Raoc, Charlotte J. Sumnera,d, and Solomon H. Snydera,e,f,2 aThe Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205; bDepartment of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205; cDepartment of Biology, Southern University of Science and Technology, Shenzhen, Guangdong, China 518055; dDepartment of Neurology and Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205; eDepartment of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and fDepartment of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205 Contributed by Solomon H. Snyder, November 8, 2017 (sent for review September 29, 2017; reviewed by Marc G. Caron and Gavril W. Pasternak) Opioids are powerful analgesics, but also carry significant side effects the field of pain biology. TRPV1 is a nociceptor activated by and abuse potential. Here we describe a modulator of the μ-opioid noxious heat, protons, and capsaicin, the pungent component of receptor (MOR1), the transient receptor potential channel subfamily chili peppers. TRPV1 is a nonselective cation channel, but pre- vanilloid member 1 (TRPV1). We show that TRPV1 binds MOR1 and dominantly fluxes calcium ions and is widely expressed in small- blocks opioid-dependent phosphorylation of MOR1 while leaving G diameter C-fiber neurons (16–18). TRPV1 is often coexpressed protein signaling intact. Phosphorylation of MOR1 initiates recruit- with MOR1 in peripheral nervous tissues, including dorsal root ment and activation of the β-arrestin pathway, which is responsible ganglion cells (DRGs), and is expressed at low levels throughout for numerous opioid-induced adverse effects, including the devel- the brain (2, 19–21).