Behavioral and Brain Sciences Plasticity: Implications for Opioid
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52Nd Annual Meeting
ACNP 52nd Annual Meeting Final Program December 8-12, 2013 The Westin Diplomat Resort & Spa Hollywood, Florida President: David A. Lewis, M.D. Program Committee Chair: Randy D. Blakely, Ph.D. Program Committee Co-Chair: Pat R. Levitt, Ph.D. This meeting is jointly sponsored by the Vanderbilt University School of Medicine Department of Psychiatry and the American College of Neuropsychopharmacology. Dear ACNP Members and Guests, It is a distinct pleasure to welcome you to the 2014 meeting of the American College of Neuropsychopharmacology! This 52nd annual meeting will again provide opportunities for the exercise of the College’s core values: the spirit of Collegiality, promoting in each other the best in science, training and service; participation in Community, pursuing together the goals of understanding the neurobiology of brain diseases and eliminating their burden on individuals and our society; and engaging in Celebration, taking the time to recognize and enjoy the contributions and accomplishments of our members and guests. Under the excellent leadership of Randy Blakely and Pat Levitt, the Program Committee has done a superb job in assembling an outstanding slate of scientific presentations. Based on membership feedback, the meeting schedule has been designed with the goals of achieving an optimal mix of topics and types of sessions, increasing the diversity of participating scientists and creating more time for informal interactions. The presentations will highlight both the breadth of the investigative interests of ACNP membership -
Design and Synthesis of Functionally Selective Kappa Opioid Receptor Ligands
Design and Synthesis of Functionally Selective Kappa Opioid Receptor Ligands By Stephanie Nicole Johnson Submitted to the graduate degree program in Medicinal Chemistry and the Graduate Faculty of the University of Kansas in partial fulfillment of the requirements for the degree of Masters in Science. Chairperson: Dr. Thomas E. Prisinzano Dr. Apurba Dutta Dr. Jeffrey P. Krise Date Defended: May 2, 2017 The Thesis Committee for Stephanie Nicole Johnson certifies that this is the approved version of the following thesis: Design and Synthesis of Functionally Selective Kappa Opioid Receptor Ligands Chairperson: Dr. Thomas E. Prisinzano Date approved: May 4, 2017 ii Abstract The ability of ligands to differentially regulate the activity of signaling pathways coupled to a receptor potentially enables researchers to optimize therapeutically relevant efficacies, while minimizing activity at pathways that lead to adverse effects. Recent studies have demonstrated the functional selectivity of kappa opioid receptor (KOR) ligands acting at KOR expressed by rat peripheral pain sensing neurons. In addition, KOR signaling leading to antinociception and dysphoria occur via different pathways. Based on this information, it can be hypothesized that a functionally selective KOR agonist would allow researchers to optimize signaling pathways leading to antinociception while simultaneously minimizing activity towards pathways that result in dysphoria. In this study, our goal was to alter the structure of U50,488 such that efficacy was maintained for signaling pathways important for antinociception (inhibition of cAMP accumulation) and minimized for signaling pathways that reduce antinociception. Thus, several compounds based on the U50,488 scaffold were designed, synthesized, and evaluated at KORs. Selected analogues were further evaluated for inhibition of cAMP accumulation, activation of extracellular signal-regulated kinase (ERK), and inhibition of calcitonin gene- related peptide release (CGRP). -
Cardioprotective Properties of Opioid Receptor Agonists in Rats with Stress-Induced
Cardioprotective Properties of Opioid Receptor Agonists in Rats with Stress-Induced Cardiac Injury Ekaterina S. Prokudinaa B, Leonid N. Maslova* A, D, E, F, Natlia V. Naryzhnayaa B,G, Sergey Yu. Tsibulnikova B,C,E, Yury B. Lishmanova,b D, John E. Madias PhD c D,E, Peter R. Oeltgen PhD d D,E aLaboratory of Experimental Cardiology, Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences 634012 Tomsk, Russia. bLaboratory of Nuclear Medicine, National Research Tomsk Polytechnic University, Tomsk, Russia. cIcahn School of Medicine at Mount Sinai, and the Division of Cardiology, Elmhurst Hospital Center, New York, New York, USA. dDepartment of Pathology, University of Kentucky College of Medicine, Lexington, KY, USA * Correspondence: Leonid N. Maslov, MD, PhD, DSci, Professor of Pathological Physiology Laboratory of Experimental Cardiology, Federal State Budgetary Scientific Institution «Research Institute for Cardiology», Kyevskaya 111A, 634012 Tomsk, Russia Tel. +7 3822 262174 E-mail address: [email protected] Short title: Stress cardiomyopathy and opioid receptors Summary Purpose The objectives of this study were to investigate the role of endogenous opioids in the mediation of stress-induced cardiomyopathy (SIC), and to evaluate which opioid receptors regulate heart resistance to immobilization stress. Methods Wistar rats were subjected to 24 h 1 immobilization stress. Stress-induced heart injury was assessed by 99mTc-pyrophosphate accumulation in the heart. The opioid receptor (OR) antagonists (naltrexone, NxMB - naltrexone methyl bromide, MR 2266, ICI 174.864) and agonists (DALDA, DAMGO, DSLET, U-50,488) were administered intraperitoneally prior to immobilization and 12 h after the start of stress. In addition, the selective µ OR agonists PL017 and DAMGO were administered intracerebroventricularly prior to stress. -
Morphine Indiscriminatingly Overstimulates All Opioid Receptors Including Those Not Involved in (Morphine) Pain Control (Exogenous)
Extensions des propriétés des inhibiteurs mixtes des enképhalinases aux douleurs de la sphère cranio-faciale. Nouvelles applications à la migraine et aux douleurs de la cornée. Bernard P. Roques Professeur Emérite, Université Paris Descartes Unité 1267 Inserm, 4 avenue de l’Observatoire, 75006 Paris. ATHS Biarritz, 1-4 Octobre 2019 CONFIDENTIAL 1 Endorphins and their receptors. Endomorphin-1 Tyr – Pro – Trp – Phe – NH2 Endomorphin-2 Tyr – Pro – Phe – Phe – NH2 2 2 Drug Discovery : designing the ideal opioid (From B.L. Kieffer, Nature (2016), 537, 170-171) 3 Three levels of pain control by endogenous opioid system (EOS) EOS EOS Attacking pain at EOS its source Relieving or reducing pain at its source More than 50% of MO effects are attributable to peripheral neurons (nociceptors) Roques, B.P., Fournié-Zaluski, M.C. and Wurm, M., Nature Reviews Drug Discovery, 2012 4 DENKIs: mechanism of action The endogenous opioid system (EOS) is present at all levels of physiological-nociceptive control i.e. periphery, spinal cord and brain Elements of the EOS are opioid receptors, enkephalins and their inactivating enzymes Dual Inhibitors of ENKephalinases (DENKIs) potentiate physiological functions of DENKI enkephalins (e.g. pain control) only on those pathways where they are tonically released Enkephalinases APN NEP No adverse effects Enkephalins Y G G F M(L) (endogenous) Opioid receptors Morphine indiscriminatingly overstimulates all opioid receptors including those not involved in (Morphine) pain control (exogenous) Adverse effects 5 Synergistic combinations of the dual enkephalinase inhibitor PL265 given orally with various analgesic compounds acting on different targets in a murine model of bone cancer-induced pain. -
Opioids Regulate Cgmp Formationin Cloned Neuroblastoma Cells
Proc. NatL. Acad. Sci. USA Vol. 79, pp. 690-694, January 1982 Neurobiology Opioids regulate cGMP formation in cloned neuroblastoma cells (cyclic nucleotides/opiate receptor/desensitization) GERMAINE J. GWYNN AND ERMINIO COSTA* Laboratory of Preclinical Pharmacology, National Institute of Mental Health, Saint Elizabeths Hospital, Washington, D.C. 20032 Communicated by Floyd E. Bloom, October 8, 1981 ABSTRACT Opioid agonists caused a rapid dose-related el- cumulation in rat striatal slices with characteristics that fulfill evation of the cGMP content of N4TG1 murine neuroblastoma the criteria for a specific narcotic action (6). In contrast, the cells. An excellent correlation was found between the rank order decrements in the cGMP content ofcerebellar tissue observed of potency of agonists in stimulating cGMP accumulation and in after morphine administration are probably indirect effects of displacing [3H]etorphine ([H]ETP) bound to intact cells. The nar- opioid receptor stimulation mediated by the modulation of y- cotic antagonists naloxone and diprenorphine failed to increase aminobutyric acid or acetylcholine collateral neuronal loops (7, cGMP content; moreover, in the presence of 5 ,IM naloxone, the 8). A functional role for cGMP in opioid action is further sug- EC50 of ETP increased from w9 nM to >1 ,uM. N4TG1 cells that had been incubated for 20 min with 0.32 ItM ETP and thoroughly gested by the pivotal role that calcium ions play both in regu- washed displayed a marked loss in sensitivity to subsequent ETP lating cGMP formation (for review, see refs. 9, 10) and in me- challenge. This desensitization was characterized by a 40-50% diating the acute and chronic effects ofopioids (for review, see decrease in maximal response and an increase in the apparent Ka refs. -
The Inhibition of Enkephalin Catabolism by Dual Enkephalinase Inhibitor: a Novel Possible Therapeutic Approach for Opioid Use Disorders
Alvarez-Perez Beltran (Orcid ID: 0000-0001-8033-3136) Maldonado Rafael (Orcid ID: 0000-0002-4359-8773) THE INHIBITION OF ENKEPHALIN CATABOLISM BY DUAL ENKEPHALINASE INHIBITOR: A NOVEL POSSIBLE THERAPEUTIC APPROACH FOR OPIOID USE DISORDERS ALVAREZ-PEREZ Beltran1*, PORAS Hervé 2*, MALDONADO Rafael1 1 Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona Biomedical Research Park, c/Dr Aiguader 88, 08003 Barcelona, Spain, 2 Pharmaleads, Paris BioPark, 11 Rue Watt, 75013 Paris, France *Both authors participated equally to the manuscript Correspondence: Rafael Maldonado, Laboratori de Neurofarmacologia, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona (PRBB), c/Dr. Aiguader, 88, 08003 Barcelona, Spain. E-mail: [email protected] ABSTRACT Despite the increasing impact of opioid use disorders on society, there is a disturbing lack of effective medications for their clinical management. An interesting innovative strategy to treat these disorders consists in the protection of endogenous opioid peptides to activate opioid receptors, avoiding the classical opioid-like side effects. Dual Enkephalinase Inhibitors (DENKIs) physiologically activate the endogenous opioid system by inhibiting the enzymes responsible for the breakdown of enkephalins, protecting endogenous enkephalins, increasing their half-lives and physiological actions. The activation of opioid receptors by the increased enkephalin levels, and their well-demonstrated safety, suggest that DENKIs could represent a novel analgesic therapy and a possible effective treatment for acute opioid withdrawal, as well as a promising alternative to opioid substitution therapy minimizing side effects. This new pharmacological class of compounds could bring effective and safe medications avoiding the This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. -
(D-Ala*)Deltorphin II: D,-Dependent Stereotypies and Stimulation of Dopamine Release in the Nucleus Accumbens
The Journal of Neuroscience, June 1991, 17(6): 1565-l 576 (D-Ala*)Deltorphin II: D,-dependent Stereotypies and Stimulation of Dopamine Release in the Nucleus Accumbens R. Longoni,’ L. Spina,’ A. Mulas,’ E. Carboni,’ L. Garau,’ P. Melchiorri,2 and G. Di Chiaral ‘Institute of Experimental Pharmacology and Toxicology, University of Cagliari, 09100 Cagliari, Italy and 21nstitute of Medical Pharmacology, University of Rome “La Sapienza,” 00185 Rome, Italy In order to investigate the relative role of central 6- and has been implicated in the stimulant actions of systemic opiates. F-opioid receptors in behavior, the effects of (D- Morphine-like opiates stimulate DA release preferentially in the Ala*)cleltorphin II, a natural Gopioid peptide, and PL017, nucleus accumbens (Di Chiara and Imperato, 1988a) and elicit a beta-casomorphin derivative specific for mu receptors, hypermotility sensitive to blockade by the DA D, receptor an- were compared after local intracerebral and intraventricular tagonist SCH 23390 (Longoni et al., 1987a). Intra-accumbens administration. lntracerebral infusion of the two peptides was infusion of opioid peptides elicits motor stimulation, but this done bilaterally in the limbic nucleus accumbens and in the action seems independent from DA, being resistant to classic ventral and dorsal caudate putamen of freely moving rats DA-receptor antagonists (neuroleptics; Pert and Sivit, 1977; Ka- through chronic intracerebral cannulas. After intra-accum- livas et al., 1983). Moreover, the syndrome elicited by intra- bens infusion, the two peptides elicited marked but opposite accumbens opiates is biphasic, as motor stimulation is typically behavioral effects: while (o-Ala2)deltorphin II evoked dose- preceded by motor inhibition and catalepsy (Costa11et al., 1978). -
(12) United States Patent (10) Patent No.: US 8.247,609 B2 Roques Et Al
USOO82476.09B2 (12) United States Patent (10) Patent No.: US 8.247,609 B2 Roques et al. (45) Date of Patent: Aug. 21, 2012 (54) AMINOACID DERIVATIVES CONTAININGA FOREIGN PATENT DOCUMENTS DSULFANYL GROUPIN THE FORM OF EP O262O53 3, 1988 MIXED DISULEANYLAND AMINOPEPTIDASEN INHIBITORS (Continued) (75) Inventors: Bernard Roques, Paris (FR): Marie-Claude Fournie-Zalluski, Paris OTHER PUBLICATIONS (FR) Silverman (The Organic Chemistry of Drug Design and Drug Action, (73) Assignee: Pharamleads, Paris (FR) 1992, Academic Press Inc.).* (*) Notice: Subject to any disclaimer, the term of this (Continued) patent is extended or adjusted under 35 U.S.C. 154(b) by 868 days. (21) Appl. No.: 12/146,941 Primary Examiner — Susanna Moore Assistant Examiner — Jennifer C Sawyer (22) Filed: Jun. 26, 2008 (74) Attorney, Agent, or Firm — Harness, Dickey & Pierce, (65) Prior Publication Data P.L.C. US 2009/OO12153 A1 Jan. 8, 2009 Related U.S. Application Data (57) ABSTRACT (63) Continuation-in-part of application No. 12/084,091, The invention relates to novel compounds of formula (I): filed as application No. PCT/EP2006/067711 on Oct. HN CH(R)-CH S S CH-CH(R) CONH 24, 2006. Rs, wherein R is a hydrocarbon chain, phenyl or benzyl (30) Foreign Application Priority Data radical, methylene radical substituted by a 5 or 6 atom het erocycle; R is a phenyl or benzyl radical, a 5 or 6 atom Oct. 25, 2005 (FR) ...................................... O5 10862 aromatic heterocycle, methylene group Substituted by a 5 or 6 May 5, 2006 (FR) ...................................... O6 O4030 atom heterocycle; Rs is a CH(R)—COOR radical, wherein R is hydrogen, an OH or OR group, a saturated hydrocarbon (51) Int. -
Npp2013281.Pdf
Neuropsychopharmacology (2013) 38, S435–S593 & 2013 American College of Neuropsychopharmacology. All rights reserved 0893-133X/13 www.neuropsychopharmacology.org Poster Session III-Wednesday participants indicated their ongoing experience of the Wednesday, December 11, 2013 intensity of heartbeat and breathing sensations by rotating a dial. Discrimination was measured by a positive dial deflection above baseline during an infusion trial. Accuracy W2. Interoceptive Awareness in Meditators During was measured via maximum cross correlation between each Cardiorespiratory Deviations in Body Arousal subject’s dial ratings and their corresponding heart rate Sahib Khalsa*, David Rudrauf, Richard Davidson, response. After each infusion participants also traced the Daniel Tranel body locations where they had felt heartbeat sensations, on a manikin template. UCLA Semel Institute for Neuroscience and Human Results: Bolus isoproterenol infusions elicited equivalent Behavior, Los Angeles, California increases in heart rate in both groups (Repeated measures ANOVA; F(1, 5) ¼ 50.1, po0.0001). There were no signifi- Background: Attention directed towards internal body cant group (F(1, 28) ¼ 1.27, p ¼ 0.27) or group x dose sensations is commonly practiced in many meditation interactions (F(1, 5) ¼ 0.04, p ¼ 0.998). There were also no traditions, and is a core skill cultivated when learning group differences in adrenergic sensitivity as measured by mindfulness. This practice is commonly proposed to CD25 (dose required to elevate heart rate by 25 beats per -
IRL Grey- B 12/28/2016 1 Protocol Version 6
IRL Grey- B 12/28/2016 RESEARCH PROTOCOL Incomplete Response in Late Life Depression: Getting to Remission with Buprenorphine Principal Investigator: Eric J. Lenze, MD Professor of Psychiatry Washington University School of Medicine Department of Psychiatry 660 S. Euclid Ave., Campus Box 8134 St. Louis, MO 63110 Voice: (314) 362-1671 E-mail: [email protected] Collaborator: Evan Kharasch, MD Vice Chancellor for Research Russell D. and Mary B. Shelden Professor of Anesthesiology Director, Division of Clinical and Translational Research Department of Anesthesiology Professor of Biochemistry and Molecular Biophysics Washington University in St. Louis 660 S Euclid Ave, Campus Box 8054 St. Louis, MO 63110-1093 [email protected] T 314-362-8796 F 314-362-8334 Pilar Cristancho, MD Assistant Professor of Psychiatry 660 S. Euclid Ave., Campus Box 8134 St. Louis, MO 63110 [email protected] 314-362-2413 Study Team Members: Julia Schweiger, CCRC – Project Manager, Psychiatry (314) 362-3153 Marissa Rhea, MA, Clinical Research Coordinator, Psychiatry (314)-362-3797 Washington University Human Research Protection Office Washington University in St. Louis 660 S. Euclid Ave., Campus Box 8089 St. Louis, MO 63110 Sponsor: National Institute of Mental Health 1 Protocol Version 6 IRL Grey- B 12/28/2016 1. Synopsis: Study Title Incomplete Response in Late Life Depression: Getting to Remission with Buprenorphine Objective 1) To test the efficacy of buprenorphine (BPN), 2) to examine safety and tolerability of buprenorphine (BPN). Study Period Planned enrollment duration: Approximately 3 years Planned study duration: Approximately 28 to 32 weeks per subject Number of Enroll approximately 100 participants, aged 50 and older, of both sexes and Patients all races Study Medication Subjects will receive an approximate 12 week course of open-label Administration venlafaxine XR. -
Rôles Des Récepteurs Nucléaires Nur77 Et Nor-1 Et Des
Rôles des récepteurs nucléaires Nur77 et Nor-1 et des neuropeptides enképhaline et dynorphine dans les comportements médiés par la dopamine et induits par les psychostimulants Thèse Céline Hodler Programme de doctorat en Neurobiologie Philosophiae doctor (Ph.D.) Faculté de médecine Québec, Canada © Céline Hodler, 2012 RÉSUMÉ Cette thèse démontre que les récepteurs nucléaires Nur77 et Nor-1 ainsi que les neuropeptides dynorphine (DYN) et enképhaline (ENK) sont des facteurs déterminants de la régulation du système dopaminergique. Notre premier manuscrit démontre d’une part que Nur77 et Nor-1 sont très clairement impliqués dans la régulation de l’homéostasie du système dopaminergique et qu’ils y jouent des rôles distincts, voire opposés, dans les conditions basales et dans les réponses comportementales et biochimiques aux psychostimulants. La délétion génétique de Nur77 augmente la proportion des récepteurs D2 en haute affinité (D2high), supprime les stéréotypies et perturbe la persistance de la préférence de place induites par l’administration répétée de psychostimulants. À l’inverse, la délétion de Nor-1 diminue la proportion des récepteurs D2high, atténue les comportements moteurs en réponse à l’amphétamine et supprime la sensibilisation comportementale. La délétion de Nor-1 module également l’expression de la DYN et de l’ENK favorisant ainsi une diminution de la réponse comportementale alors que celle de Nur77 induit l’effet inverse. Ainsi, Nor-1 et Nur77 jouent des rôles opposés, la délétion de Nor-1 tempère les comportements moteurs, celle de Nur77 les exacerbe. Notre second manuscrit démontre d’autre part que la DYN et l’ENK sont toutes deux nécessaires et ont des rôles opposés dans la manifestation des comportements de base médiés par la dopamine. -
Replacement of Current Opioid Drugs Focusing on MOR-Related Strategies
JPT-107519; No of Pages 17 Pharmacology & Therapeutics xxx (2020) xxx Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Replacement of current opioid drugs focusing on MOR-related strategies Jérôme Busserolles a,b, Stéphane Lolignier a,b, Nicolas Kerckhove a,b,c, Célian Bertin a,b,c, Nicolas Authier a,b,c, Alain Eschalier a,b,⁎ a Université Clermont Auvergne, INSERM, CHU, NEURO-DOL Pharmacologie Fondamentale et Clinique de la douleur, F-63000 Clermont-Ferrand, France b Institut ANALGESIA, Faculté de Médecine, F-63000 Clermont-Ferrand, France c Observatoire Français des Médicaments Antalgiques (OFMA), French monitoring centre for analgesic drugs, CHU, F-63000 Clermont-Ferrand, France article info abstract Available online xxxx The scarcity and limited risk/benefit ratio of painkillers available on the market, in addition to the opioid crisis, warrant reflection on new innovation strategies. The pharmacopoeia of analgesics is based on products that are often old and derived from clinical empiricism, with limited efficacy or spectrum of action, or resulting in Keywords: an unsatisfactory tolerability profile. Although they are reference analgesics for nociceptive pain, opioids are sub- Analgesia ject to the same criticism. The use of opium as an analgesic is historical. Morphine was synthesized at the begin- Mu opioid receptors (MORs) ning of the 19th century. The efficacy of opioids is limited in certain painful contexts and these drugs can induce Opioid adverse side effects potentially serious and fatal adverse effects. The current North American opioid crisis, with an ever-rising number Opioid abuse and misuse of deaths by opioid overdose, is a tragic illustration of this.