Proquest Dissertations

Total Page:16

File Type:pdf, Size:1020Kb

Proquest Dissertations Mechanisms of reduced opioid effectiveness in a rat model of neuropathic pain Item Type text; Dissertation-Reproduction (electronic) Authors Nichols, Michael Lorne, 1967- Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 24/09/2021 16:21:32 Link to Item http://hdl.handle.net/10150/282342 INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter &ce, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. In the imlikely event that the author did not send UME a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand comer and continuing from left to right in equal sections with small overlaps. Each original is also photographed in one exposure and is included in reduced form at the back of the book. Photographs included in the original manuscript have been reproduced xerographically in this copy. Higher quality 6" x 9" black and white photographic prints are available for any photographs or illustrations appearing in this copy for an additional charge. Contact UMI directly to order. UMI A Bell & Howell Infonnation Company 300 North Zeeb Road, Ann Aibor MI 48106-1346 USA 313/761-4700 800/521-0600 Mechanisms of Reduced Opioid Effectiveness in a Rat Model of Neuropathic Pain by Michael Lome Nichols A Dissertation Submitted to the Faculty of the COMMITTEE ON PHARMACOLOGY AND TOXICOLOGY (Graduate) In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY In the Graduate College THE UNIVERSITY OF ARIZONA 1997 UMI Nximber: 9729518 UMI Microform 9729518 Copyright 1997, by UMI Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. UMI 300 North Zeeb Road Ann Arirar, MI 48103 2 THE UNIVERSITY OF ARIZONA ® GRADUATE COLLEGE As members of the Final Examination Committee, we certify that we have read the dissertation prepared by Michael L. Nichols entitled Mechanisms of Reduced Opioid Effectiveness in a Rat Model of Neuropathic Pain and recommend that it be accepted as fulfilling the dissertation requirement for tlie Degree of Doctor of Philosophy OA.KSLCS. 4-- FV^k Porr^a,^h.D. Date ^9-^7 Edward D. , Ph.D. Date Lai, Ph.D. Date r. PhUlilsCMa^./M.D'./,In,/;M.D^, Ph.D. Date H-lih7 D. Palmer, M.D., Ph.D. Date Final approval and acceptance of this dissertation is contingent upon the candidate's submission of the final copy of the dissertation to the Graduate College. I hereby certify that I have read this dissertation prepared under my direction and re^mmend that it be accepted as fulfilling the dissertation requirement. hAiAlt. f ~/0 -^1 Usfeertation Director Date 3 STATEMENT BY AUTHOR This dissertation has been submitted in partial fulfillment of requirements for an advanced degree at The University of Arizona and is deposited in the University Library to be made available to borrowers under mles of the Library. Brief quotations from this dissertation are allowable without special permission, provided that accurate acknowledgment of source is made. Requests for permission for extended quotation from or reproduction of this manuscript in whole or in part may be granted by the head of the major department or the Dean of the Graduate College when in his or her judgment the proposed use of the m ^ * • ^ ' ' hip. In all other instances, however, permission must be 4 ACKNOWLEDGEMENTS I thank Dr. Frank Porreca for giving me the opportunity to be successful when no one else would. Frank has provided me with an excellent setting to develop and excel as a young scientist. Further, Frank has given me both the guidance, motivation and example of a true mentor. I also thank my conunittee members, Drs. Ed French, Josephine Lai. Phil Malan and John Palmer for their time and effort to help me complete my Ph.D. I also thank Dr. Larry Reid everything he has given me along the way. Di (Chuck) Bian and Michael (Rash) Ossipov deserve special recognition. Chuck has worked with me on nearly every project in the laboratory, and his surgical skills have saved me countless hours of frustration. Mike O. has helped me through my confusion with his expertise and guidance. On the intellectual side of things he has given his all to help me understand. I thank them both very much. I have shared many things with Ed (Dr. Dork) Bilsky, including office space, for the greater part of nearly twelve years. Ed has been a great friend who has kept the lab from feeling like a job. I will dearly miss Ed and his antics and I wish him and his lovely wife, Jill, all the best. Other members of the Porreca tribe that deserve recognition are Joe Tumminia, C.J. (Squeegee) Kovelowski, Dr. Todd (Squirrel) Vanderah, Dr. Robert (Bob) Horvath, Sandy (Flower) Wegert, Eddie Mata, Dr. Ken (Vem) Wild and Jason Lashbrook for always lending a hand or an ear to me along the way. I consider all of you my friends. I also thank all of the friends I have made in Arizona including Ray-ray, Steve Stratton, Lungs of a Smoker (Jill, Kent, AI, Mr. Potatohead and EFang), softball teamates and camping crews. Russ (Crusty) Ingersoll is my dear friend, whom I'll miss very much. Lastly, I thank my best friend, Wanda, who has not only been my friend, but has managed to survive living with me for nearly four years. I love you very much, Wanda. 5 DEDICATION This disseration is dedicated to my parents, Robert and Marie Nichols. Their sacrifice gave me the opportunity to begin my academic career. Their support helped to propel me through my bachelor's, master's, and now, my doctoral degree. I would never have been given these opportunities without them. 6 TABLE OF CONTENTS Page LIST OF ILLUSTRATIONS 13 ABSTRACT 20 INTRODUCTION 22 Nociception 23 The neurotransmission of pain 25 Hyperalgesia 27 Opiates and opioids and pain perception 30 Brief history 30 Opioid receptors and endogenous opioids 31 Opioids and the inhibition of pain 36 Endogenous pain control 40 Abnormal pain states: peripheral neuropathy 41 Animal models of peripheral neuropathy 43 Opiates in neuropathic pain 44 Excitatory amino acids and neuropathic pain 46 7 TABLE OF CONTENTS-ConfmueJ Page The non-opioid effects of dynorphin and neuropathic pain 49 Afferent fibers and neuropathic pain 50 Modulation of the effectiveness of mu opiates (morphine) 52 HYPOTHESIS OF THE DISSERTATION 57 Hypothesis 1 57 Hypothesis 2 57 Hypothesis 3 58 METHODS 59 Animals 59 Chemicals 59 Surgical implantation of the intrathecal catheter 60 Drug administration 61 L5/L6 nerve ligation and sham surgery 62 Neonatal capsaicin treatment 63 Behavioral Testing 63 von Frey assay (including normalized von Frey fibers) 63 8 TABLE OF CONTENTS- Continued Page Warm-water tail flick assay 64 Radiant heat foot flick assay 65 Pin prick assay 65 Statistics 65 RESULTS OF PRELIMINARY EXPERIMENTS 67 Baseline testing 67 Testing with normalized von Frey fllaments 68 Effect of anesthetic on the development of tactile allodynia 71 SUMMARY OF PRELIMINARY EXPERIMENTS 77 RESULTS OF STUDIES INVOLVING OPIATES AND OPIOIDS 79 Lack of effect of intrathecal morphine to probing with von Frey monofilaments 79 Reduced antinociceptive effectiveness of morphine in rats with nerve-ligation injury 83 Studies on the effect of intrathecal [D-Ala^, NMePhe^, Gly- oljenkephalin (DAMGO) to probing with von Frey monofilaments. .83 9 TABLE OF CONTENTS- Continued Page Studies on the antiallodynic effect of intrathecal SNC 80 in rats with nerve injury 88 Studies on the antiallodynic effect of intrathecal [D-Ala^, Glu^ldeltorphin in rats with nerve injury 90 Studies on the antiallodynic effect of intrathecal biphalin in rats with nerve injury 93 Studies on the antiallodynic effect of intrathecally administered kappa agonists in rats with nerve injury 97 SUMMARY OF STUDIES INVOLVING OPIATES AND OPIOIDS 100 RESULTS OF EXPERIMENTS INVOLVING NEONATAL CAPSAICIN TREATMENT 106 Effects of capsaicin treatment on nociceptive thresholds 106 Warm-water Tail Flick {48'C) 106 Warm-water Tail Flick (52"C) 107 Radiant Heat Paw Withdrawal 107 Pin Prick 110 10 TABLE OF CONTENTS- Continued Page Von Frey probing 110 Effects of morphine in capsaicin treated rats 114 Morphine in the warm-water tail flick (52" C) 114 Morphine in the von Frey assay 120 Effects of DAMGO in capsaicin treated rats 123 DAM GO in the warm-water tail flick (52" C) 123 DAMGO in the von Frey assay 129 SUMMARY OF EXPERIMENTS INVOLVING NEONATAL CAPSAICIN TREATMENT 134 RESULTS OF EXPERIMENTS INVOLVING EXCITATORY AMINO ACID ANTAGONISTS AND DYNORPHIN A (1-13) ANTISERA 140 Studies on the antiallodynic effects of excitatory amino acid antagonists 140 MK 801 versus tactile allodynia 140 CNQX versus tactile allodynia 142 L-AP3 versus tactile allodynia 142 11 TABLE OF CONTENTS- Continued Page Studies on the effects of morphine in the presence of MK 801 148 Tactile allodynia 148 Warm-water tail flick (55°C) 151 Studies on the effect of morphine following pretreatment with antisera to dynorphin A (1-13) 154 Tactile allodynia 154 Warm-water tail flick 55"C 154 SUMMARY OF EXPERIMENTS INVOLVING EXCITATORY AMINO ACID ANTAGONISTS AND DYNORPHIN A (1-13) ANTISERA 159 RESULTS OF EXPERIMENTS INVOLVING DYNORPHIN A (1-17) 163 SUMMARY OF EXPERIMENTS INVOLVING DYNORPHIN A (1-17)..
Recommended publications
  • (Apis Mellifera) ELISABETH P
    J. Insect Ph.vsiol. Vol. 42, No. 9, pp. 823-828, 1996 Pergamon Copyright 0 1996 Elsevier Science Ltd Printed in Great Britain. All rights reserved PII: SOO22-1910(96)00045-5 0022-1910196 $15.00 + 0.00 Effects of Two Proteinase Inhibitors on the Digestive Enzymes and Survival of Honey Bees (Apis mellifera) ELISABETH P. J. BURGESS,*1 LOUISE A. MALONE,* JOHN T. CHRlSTELLERt Received I1 December 1995; revised und accepted 1 March 1996 Two endopeptidase inhibitors, BPTI (bovine pancreatic trypsin inhibitor) and SBTI (Kunitz soybean trypsin inhibitor), were found to significantly reduce the longevity of adult honey bees (&is mellifera L.) fed the inhibitors ad lib in sugar syrup at l.O%, 0.5% or O.l%, but not at 0.01% or 0.001% (w:v). Bees were taken from frames at emergence, kept in cages at 33”C, and provided with a pollen/protein diet, water and syrup. In vivo activity levels of three midgut endopeptidases (trypsin, chymotrypsin and elastase) and the exopeptidase leucine aminopeptidase (LAP) were determined in bees fed either BPTI or SBTI at l.O%, 0.3% or 0.1% (w:v) at two time points: the 8th day after emergence and when 75% of bees had died. LAP activity levels increased significantly in bees fed with either inhibitor at all concen- trations. At day 8, bees fed BPTI at all concentrations had significantly reduced levels of trypsin, chymotrypsin and elastase. At the time of 75% mortality, bees fed BPTI at each concentration had reduced trypsin levels, but only those fed the inhibitor at the highest dose level had reduced chymotrypsin or elastase activity.
    [Show full text]
  • Treatment Protocol Copyright © 2018 Kostoff Et Al
    Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al PREVENTION AND REVERSAL OF ALZHEIMER'S DISEASE: TREATMENT PROTOCOL by Ronald N. Kostoffa, Alan L. Porterb, Henry. A. Buchtelc (a) Research Affiliate, School of Public Policy, Georgia Institute of Technology, USA (b) Professor Emeritus, School of Public Policy, Georgia Institute of Technology, USA (c) Associate Professor, Department of Psychiatry, University of Michigan, USA KEYWORDS Alzheimer's Disease; Dementia; Text Mining; Literature-Based Discovery; Information Technology; Treatments Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al CITATION TO MONOGRAPH Kostoff RN, Porter AL, Buchtel HA. Prevention and reversal of Alzheimer's disease: treatment protocol. Georgia Institute of Technology. 2018. PDF. https://smartech.gatech.edu/handle/1853/59311 COPYRIGHT AND CREATIVE COMMONS LICENSE COPYRIGHT Copyright © 2018 by Ronald N. Kostoff, Alan L. Porter, Henry A. Buchtel Printed in the United States of America; First Printing, 2018 CREATIVE COMMONS LICENSE This work can be copied and redistributed in any medium or format provided that credit is given to the original author. For more details on the CC BY license, see: http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License<http://creativecommons.org/licenses/by/4.0/>. DISCLAIMERS The views in this monograph are solely those of the authors, and do not represent the views of the Georgia Institute of Technology or the University of Michigan. This monograph is not intended as a substitute for the medical advice of physicians. The reader should regularly consult a physician in matters relating to his/her health and particularly with respect to any symptoms that may require diagnosis or medical attention.
    [Show full text]
  • Combined Neprilysin and Renin–Angiotensin System Inhibition in Heart Failure with Reduced Ejection Fraction: a Meta-Analysis
    European Journal of Heart Failure (2016) doi:10.1002/ejhf.603 Combined neprilysin and renin–angiotensin system inhibition in heart failure with reduced ejection fraction: a meta-analysis Scott D. Solomon1*, Brian Claggett1, John J.V. McMurray2, Adrian F. Hernandez3, and Gregg C. Fonarow4 1Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 2University of Glasgow, Glasgow, UK; 3Duke University, Durham, NC, USA; and 4Ronald Reagan-UCLA Medical Center, Los Angeles, CA, USA Received 1 March 2016; revised 25 May 2016; accepted 3 June 2016 Aims The combined neprilysin/renin–angiotensin system (RAS) inhibitor sacubitril/valsartan reduced cardiovascular death or heart failure hospitalization, cardiovascular death, and all-cause mortality in a large outcomes trial. While sacubitril/valsartan is the only currently available drug in its class, there are two prior clinical trials in heart failure with omapatrilat, another combined neprilysin/RAS inhibitor. Using all available evidence can inform clinicians and policy-makers. ..................................................................................................................................................................... Methods We performed a meta-analysis using data from three trials in heart failure with reduced EF that compared combined and results neprilysin/RAS inhibition with RAS inhibition alone and reported clinical outcomes: IMPRESS (n = 573), OVERTURE (n = 5770), and PARADIGM-HF (n = 8399). We assessed the pooled hazard ratio (HR) for all-cause death or heart failure hospitalization, and for all-cause mortality in random-effects models, comparing combined neprilysin/RAS inhibition with ACE inhibition alone. The composite outcome of death or heart failure hospitalization was reduced numerically in patients receiving combined neprilysin/RAS inhibition in all three trials, with a pooled HR of 0.86, 95% confidence interval (CI) 0.76–0.97, P = 0.013.
    [Show full text]
  • Metabolic Actions of Natriuretic Peptides and Therapeutic Potential in the Metabolic Syndrome
    Pharmacology & Therapeutics 144 (2014) 12–27 Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Associate editor: G. Eisenhofer Metabolic actions of natriuretic peptides and therapeutic potential in the metabolic syndrome Nina Schlueter a,AnitadeSterkea, Diana M. Willmes a, Joachim Spranger a, Jens Jordan b,AndreasL.Birkenfelda,⁎ a Department of Endocrinology, Diabetes and Nutrition, Center for Cardiovascular Research, Charité, University School of Medicine, Berlin, Germany b Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany article info abstract Available online 27 April 2014 Natriuretic peptides (NPs) are a group of peptide-hormones mainly secreted from the heart, signaling via c-GMP coupled receptors. NP are well known for their renal and cardiovascular actions, reducing arterial blood pressure Keywords: as well as sodium reabsorption. Novel physiological functions have been discovered in recent years, including Natriuretic peptides activation of lipolysis, lipid oxidation, and mitochondrial respiration. Together, these responses promote white ANP adipose tissue browning, increase muscular oxidative capacity, particularly during physical exercise, and protect BNP against diet-induced obesity and insulin resistance. Exaggerated NP release is a common finding in congestive Insulin resistance heart failure. In contrast, NP deficiency is observed in obesity and in type-2 diabetes, pointing to an involvement Diabetes fi Obesity of NP in the pathophysiology of metabolic disease. Based upon these ndings, the NP system holds the potential to be amenable to therapeutical intervention against pandemic diseases such as obesity, insulin resistance, and arterial hypertension. Various therapeutic approaches are currently under development. This paper reviews the current knowledge on the metabolic effects of the NP system and discusses potential therapeutic applications.
    [Show full text]
  • NINDS Custom Collection II
    ACACETIN ACEBUTOLOL HYDROCHLORIDE ACECLIDINE HYDROCHLORIDE ACEMETACIN ACETAMINOPHEN ACETAMINOSALOL ACETANILIDE ACETARSOL ACETAZOLAMIDE ACETOHYDROXAMIC ACID ACETRIAZOIC ACID ACETYL TYROSINE ETHYL ESTER ACETYLCARNITINE ACETYLCHOLINE ACETYLCYSTEINE ACETYLGLUCOSAMINE ACETYLGLUTAMIC ACID ACETYL-L-LEUCINE ACETYLPHENYLALANINE ACETYLSEROTONIN ACETYLTRYPTOPHAN ACEXAMIC ACID ACIVICIN ACLACINOMYCIN A1 ACONITINE ACRIFLAVINIUM HYDROCHLORIDE ACRISORCIN ACTINONIN ACYCLOVIR ADENOSINE PHOSPHATE ADENOSINE ADRENALINE BITARTRATE AESCULIN AJMALINE AKLAVINE HYDROCHLORIDE ALANYL-dl-LEUCINE ALANYL-dl-PHENYLALANINE ALAPROCLATE ALBENDAZOLE ALBUTEROL ALEXIDINE HYDROCHLORIDE ALLANTOIN ALLOPURINOL ALMOTRIPTAN ALOIN ALPRENOLOL ALTRETAMINE ALVERINE CITRATE AMANTADINE HYDROCHLORIDE AMBROXOL HYDROCHLORIDE AMCINONIDE AMIKACIN SULFATE AMILORIDE HYDROCHLORIDE 3-AMINOBENZAMIDE gamma-AMINOBUTYRIC ACID AMINOCAPROIC ACID N- (2-AMINOETHYL)-4-CHLOROBENZAMIDE (RO-16-6491) AMINOGLUTETHIMIDE AMINOHIPPURIC ACID AMINOHYDROXYBUTYRIC ACID AMINOLEVULINIC ACID HYDROCHLORIDE AMINOPHENAZONE 3-AMINOPROPANESULPHONIC ACID AMINOPYRIDINE 9-AMINO-1,2,3,4-TETRAHYDROACRIDINE HYDROCHLORIDE AMINOTHIAZOLE AMIODARONE HYDROCHLORIDE AMIPRILOSE AMITRIPTYLINE HYDROCHLORIDE AMLODIPINE BESYLATE AMODIAQUINE DIHYDROCHLORIDE AMOXEPINE AMOXICILLIN AMPICILLIN SODIUM AMPROLIUM AMRINONE AMYGDALIN ANABASAMINE HYDROCHLORIDE ANABASINE HYDROCHLORIDE ANCITABINE HYDROCHLORIDE ANDROSTERONE SODIUM SULFATE ANIRACETAM ANISINDIONE ANISODAMINE ANISOMYCIN ANTAZOLINE PHOSPHATE ANTHRALIN ANTIMYCIN A (A1 shown) ANTIPYRINE APHYLLIC
    [Show full text]
  • Cholecystokinin Octapeptide Antagonized Opioid Analgesia Mediated by /T- and R- but Not Cs-Receptors in the Spinal Cord of the Rat
    Brain Research, 523 (1990) 5-10 5 Elsevier BRES 15696 Cholecystokinin octapeptide antagonized opioid analgesia mediated by /t- and r- but not cS-receptors in the spinal cord of the rat Xiao-Jing Wang, Xiao-Hong Wang and Ji-Sheng Han Department of Physiology, Beijing Medical University, Beijing (People's Republic of China) (Accepted 23 January 1990) Key words: Cholecystokinin octapeptide; (N-MePhea,o-Pro4) Morphiceptin; (N-MeTyrl,N-MeArg7,D-Leu 8) Dynorphin(1-8) ethylamide; (D-Pen 2'5) Enkephalin; Proglumide; Intrathecal injection; Opioid analgesia; Antiopioid effect Intrathecal (ith) injection of cholecystokinin octapeptide (CCK-8) to the rat with single dose of 4 or 40 ng, or successive doses from 0.1 to 1/ag at 10 rain intervals produced neither analgesia nor hyperalgesia. However, the analgesia produced by ith injection of PL017, a specific /~-reeeptor agonist or 66A-078, a specific r-receptor agonist could be markedly antagonized by CCK-8 at a dose as small as 4 ng. In contrast, analgesia produced by ith injection of 6-agonist DPDPE could not be blocked by CCK-8 even at a dose as high as 40 ng. Since the effect of CCK-8 could be totally reversed by the CCK receptor antagonist proglumide, this effect is most probably mediated by CCK receptors. INTRODUCTION MATERIALS AND METHODS Cholecystokinin octapeptide (CCK-8) has been known Surgical procedures and intrathecal injection of drugs Male Wistar rats weighing 200-250 g were anesthetized with as a neuropeptide of abundant and wide distribution in chlorohydrate (0.4 g/kg, i.p.). PE-10 polyethiene catheter of 7.5 cm CNS 1 with some important physiological functions in- long was implanted through the atlanto-occipital membrane down to cluding the anti-opioid effect4'9.
    [Show full text]
  • The Evolution of Heart Failure with Reduced Ejection Fraction Pharmacotherapy: What Do We Have and Where Are We Going?
    Pharmacology & Therapeutics 178 (2017) 67–82 Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Associate editor: M. Curtis The evolution of heart failure with reduced ejection fraction pharmacotherapy: What do we have and where are we going? Ahmed Selim, Ronald Zolty, Yiannis S. Chatzizisis ⁎ Division of Cardiovascular Medicine, University of Nebraska Medical Center, Omaha, NE, USA article info abstract Available online 21 March 2017 Cardiovascular diseases represent a leading cause of mortality and increased healthcare expenditure worldwide. Heart failure, which simply describes an inability of the heart to meet the body's needs, is the end point for many Keywords: other cardiovascular conditions. The last three decades have witnessed significant efforts aiming at the discovery Heart failure of treatments to improve the survival and quality of life of patients with heart failure; many were successful, Reduced ejection fraction while others failed. Given that most of the successes in treating heart failure were achieved in patients with re- Pharmacotherapy duced left ventricular ejection fraction (HFrEF), we constructed this review to look at the recent evolution of Novel drugs HFrEF pharmacotherapy. We also explore some of the ongoing clinical trials for new drugs, and investigate poten- tial treatment targets and pathways that might play a role in treating HFrEF in the future. © 2017 Elsevier Inc. All rights reserved. Contents 1. Introduction..............................................
    [Show full text]
  • Expression of POMC, Detection of Precursor Proteases, and Evidence
    ORIGINAL ARTICLE See related commentary on page 1934 Human Mast Cells in the Neurohormonal Network: Expression of POMC, Detection of Precursor Proteases, and Evidence for IgE-Dependent Secretion of a-MSH Metin Artuc1, Markus Bo¨hm2, Andreas Gru¨tzkau1, Alina Smorodchenko1, Torsten Zuberbier1, Thomas Luger2 and Beate M. Henz1 Human mast cells have been shown to release histamine in response to the neuropeptide a-melanocyte- stimulating hormone (a-MSH), but it is unknown whether these cells express proopiomelanocortin (POMC) or POMC-derived peptides. We therefore examined highly purified human skin mast cells and a leukemic mast cell line-1 (HMC-1) for their ability to express POMC and members of the prohormone convertase (PC) family known to process POMC. Furthermore, we investigated whether these cells store and secrete a-MSH. Reverse transcriptase-PCR (RT-PCR) analysis revealed that both skin mast cells and HMC-1 cells express POMC mRNA and protein. Expression of the POMC gene at the RNA level in HMC-1 cells could be confirmed by Northern blotting. Transcripts for both PC1 and furin convertase were detectable in skin-derived mast cells and HMC-1 cells, as shown by RT-PCR. In contrast, PC2 transcripts were detected only in skin mast cells, whereas transcripts for paired basic amino acid converting enzyme 4 (PACE4) were present only in HMC-1 cells. Radio- immunoassays performed on cell lysates and cell culture supernatants from human skin-derived mast cells disclosed immunoreactive amounts of a-MSH in both fractions. Stimulation with an anti-IgE antibody significantly reduced intracellular a-MSH and increased extracellular levels, indicating IgE-mediated secretion of this neuropeptide.
    [Show full text]
  • Lack of Rapid Antidepressant Effects of Kir4.1 Channel Inhibitors in A
    Pharmacology, Biochemistry and Behavior 176 (2019) 57–62 Contents lists available at ScienceDirect Pharmacology, Biochemistry and Behavior journal homepage: www.elsevier.com/locate/pharmbiochembeh Lack of rapid antidepressant effects of Kir4.1 channel inhibitors in a chronic social defeat stress model: Comparison with (R)-ketamine T Zhongwei Xionga,b, Kai Zhanga, Tamaki Ishimaa, Qian Rena, Min Maa, Yaoyu Pua, Lijia Changa, ⁎ Jincao Chenb, Kenji Hashimotoa, a Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan b Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, PR China ARTICLE INFO ABSTRACT Keywords: A recent study demonstrated a key role of astroglial potassium channel Kir4.1 in the lateral habenula in de- Antidepressant pression. We investigated whether Kir4.1 protein is altered in the brain regions from susceptible mice after a Kir4.1 channel chronic social defeat stress (CSDS). Furthermore, we compared the rapid and sustained antidepressant actions of (R)-Ketamine Kir4.1 inhibitors (quinacrine and sertraline) and (R)-ketamine, (R)-enantiomer of rapid-acting antidepressant Social defeat stress model (R,S)-ketamine, in a CSDS model. Western blot analysis of Kir4.1 protein in the brain regions (prefrontal cortex, nucleus accumbens, hippocampus) from CSDS susceptible mice and control mice (no CSDS) was performed. Quinacrine (15, or 30 mg/kg), sertraline (20 mg/kg), (R)-ketamine (10 mg/kg), or vehicle was administered intraperitoneally to CSDS susceptible mice. Subsequently, locomotion test, tail suspension test (TST), forced swimming test (FST) and 1% sucrose preference test (SPT) were performed. There were no changes of Kir4.1 protein in the all regions between two groups.
    [Show full text]
  • Diamandis Thesis
    !"!#$ CHEMICAL GENETIC INTERROGATION OF NEURAL STEM CELLS: PHENOTYPE AND FUNCTION OF NEUROTRANSMITTER PATHWAYS IN NORMAL AND BRAIN TUMOUR INITIATING NEURAL PRECUSOR CELLS by Phedias Diamandis A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy. Department of Molecular Genetics University of Toronto © Copyright by Phedias Diamandis 2010 Phenotype and Function of Neurotransmitter Pathways in Normal and Brain Tumor Initiating Neural Precursor Cells Phedias Diamandis Doctor of Philosophy Department of Molecular Genetics University of Toronto 2010 &'(!)&*!% The identification of self-renewing and multipotent neural stem cells (NSCs) in the mammalian brain brings promise for the treatment of neurological diseases and has yielded new insight into brain cancer. The complete repertoire of signaling pathways that governs these cells however remains largely uncharacterized. This thesis describes how chemical genetic approaches can be used to probe and better define the operational circuitry of the NSC. I describe the development of a small molecule chemical genetic screen of NSCs that uncovered an unappreciated precursor role of a number of neurotransmitter pathways commonly thought to operate primarily in the mature central nervous system (CNS). Given the similarities between stem cells and cancer, I then translated this knowledge to demonstrate that these neurotransmitter regulatory effects are also conserved within cultures of cancer stem cells. I then provide experimental and epidemiologically support for this hypothesis and suggest that neurotransmitter signals may also regulate the expansion of precursor cells that drive tumor growth in the brain. Specifically, I first evaluate the effects of neurochemicals in mouse models of brain tumors. I then outline a retrospective meta-analysis of brain tumor incidence rates in psychiatric patients presumed to be chronically taking neuromodulators similar to those identified in the initial screen.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2011/0263526 A1 SATYAM (43) Pub
    US 20110263526A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0263526 A1 SATYAM (43) Pub. Date: Oct. 27, 2011 (54) NITRICOXIDE RELEASING PRODRUGS OF CD7C 69/96 (2006.01) THERAPEUTICAGENTS C07C 319/22 (2006.01) CD7C 68/02 (2006.01) (75) Inventor: Apparao SATYAM, Mumbai (IN) A6IP 29/00 (2006.01) A6IP 9/00 (2006.01) (73) Assignee: PIRAMAL LIFE SCIENCES A6IP37/08 (2006.01) LIMITED, Mumbai (IN) A6IP35/00 (2006.01) A6IP 25/24 2006.O1 (21) Appl. No.: 13/092.245 A6IP 25/08 308: A6IP3L/04 2006.O1 (22) Filed: Apr. 22, 2011 A6IP3L/2 308: Related U.S. Application Data 39t. O 308: (60) Provisional application No. 61/327,175, filed on Apr. A6IP3/10 (2006.01) 23, 2010. A6IPL/04 (2006.01) A6IP39/06 (2006.01) Publication Classification A6IP3/02 (2006.01) (51) Int. Cl. A6IP 9/06 (2006.01) A 6LX 3L/7072 (2006.01) 39t. W 308: A6 IK3I/58 (2006.01) A6IP II/08 (2006.015 A6 IK3I/55 (2006.01) A63/62 (2006.015 A6 IK 3/495 (2006.01) A6 IK 3/4439 (2006.01) (52) U.S. Cl. ........... 514/50: 514/166; 514/172: 514/217; A6 IK 3L/455 (2006.01) 514/255.04: 514/338; 514/356; 514/412; A6 IK 3/403 (2006.01) 514/420; 514/423: 514/510,536/28.53:540/67; A6 IK 3/404 (2006.01) 540/591; 544/396; 546/273.7: 546/318: 548/452: A6 IK 3/40 (2006.01) 548/500: 548/537; 549/464; 558/275 A6 IK3I/265 (2006.01) C7H 9/06 (2006.01) (57) ABSTRACT CO7I 71/00 (2006.01) CO7D 22.3/26 (2006.01) The present invention relates to nitric oxide releasing pro C07D 295/14 (2006.01) drugs of known drugs or therapeutic agents which are repre CO7D 40/12 (2006.01) sented herein as compounds of formula (I) wherein the drugs CO7D 213/80 (2006.01) or therapeutic agents contain one or more functional groups C07D 209/52 (2006.01) independently selected from a carboxylic acid, an amino, a CO7D 209/26 (2006.01) hydroxyl and a sulfhydryl group.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2015/0202317 A1 Rau Et Al
    US 20150202317A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0202317 A1 Rau et al. (43) Pub. Date: Jul. 23, 2015 (54) DIPEPTDE-BASED PRODRUG LINKERS Publication Classification FOR ALPHATIC AMNE-CONTAINING DRUGS (51) Int. Cl. A647/48 (2006.01) (71) Applicant: Ascendis Pharma A/S, Hellerup (DK) A638/26 (2006.01) A6M5/9 (2006.01) (72) Inventors: Harald Rau, Heidelberg (DE); Torben A 6LX3/553 (2006.01) Le?mann, Neustadt an der Weinstrasse (52) U.S. Cl. (DE) CPC ......... A61K 47/48338 (2013.01); A61 K3I/553 (2013.01); A61 K38/26 (2013.01); A61 K (21) Appl. No.: 14/674,928 47/48215 (2013.01); A61M 5/19 (2013.01) (22) Filed: Mar. 31, 2015 (57) ABSTRACT The present invention relates to a prodrug or a pharmaceuti Related U.S. Application Data cally acceptable salt thereof, comprising a drug linker conju (63) Continuation of application No. 13/574,092, filed on gate D-L, wherein D being a biologically active moiety con Oct. 15, 2012, filed as application No. PCT/EP2011/ taining an aliphatic amine group is conjugated to one or more 050821 on Jan. 21, 2011. polymeric carriers via dipeptide-containing linkers L. Such carrier-linked prodrugs achieve drug releases with therapeu (30) Foreign Application Priority Data tically useful half-lives. The invention also relates to pharma ceutical compositions comprising said prodrugs and their use Jan. 22, 2010 (EP) ................................ 10 151564.1 as medicaments. US 2015/0202317 A1 Jul. 23, 2015 DIPEPTDE-BASED PRODRUG LINKERS 0007 Alternatively, the drugs may be conjugated to a car FOR ALPHATIC AMNE-CONTAINING rier through permanent covalent bonds.
    [Show full text]