DOCSLIB.ORG

Upregulated by Cocaine in Fatal Overdose Victims

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Upregulated by Cocaine in Fatal Overdose Victims The Journal of Neuroscience, November 1, 1997, 17(21):8225–8233 k2 Opioid Receptors in Limbic Areas of the Human Brain Are Upregulated by Cocaine in Fatal Overdose Victims Julie K. Staley,1 Richard B. Rothman,2 Kenner C. Rice,3 John Partilla,2 and Deborah C. Mash1 1Department of Neurology and Molecular and Cellular Pharmacology and The Comprehensive Drug Research Center, University of Miami School of Medicine, Miami, Florida 33101, 2Clinical Psychopharmacology Section, Division of Intramural Research, National Institute on Drug Abuse, National Institutes of Health, Addiction Research Center, Baltimore, Maryland 21224, and 3Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892 Cocaine is thought to be addictive because chronic use bremazocine .. U50,488 $ U69,593) distinct from either the k1 125 leads to molecular adaptations within the mesolimbic dopa- or k3 receptor subtypes. Visualization of [ I]IOXY labeling mine (DA) circuitry that affect motivated behavior and emo- revealed that k2 receptors localize to mesocortical and subcor- tion. Although the reinforcing effects of cocaine are mediated tical limbic areas, including the cingulate, entorhinal, insular, primarily by blocking DA reuptake into the presynaptic nerve and orbitofrontal cortices and the nucleus accumbens and terminal, reciprocal signaling between DA and endogenous amygdala. The number of k2 receptors in the nucleus accum- opioids has important implications for cocaine dependence. bens and other limbic brain regions from cocaine fatalities was The present study used the opioid antagonist 6 b-[125iodo]- increased twofold as compared with age-matched and drug- 3,14-dihydroxy-17-cyclopropylmethyl-4,5 a-epoxymorphinan free control subjects. Cocaine overdose victims, who experi- ([ 125I]IOXY) after pretreatment with the site-directed acylating enced paranoia and marked agitation before death, also had agents 2-( p-ethoxybenzyl)-1-diethylaminoethyl-5-isothiocyanato- elevated densities of k2 receptors in the amygdala. These benzimidiazole-HCl (m-selective) and N-phenyl-N-[1-(2-(4- findings demonstrate for the first time that k2 receptor numbers isothiocyanato)-phenethyl)-4-piperidinyl]-propanamide-HCl (d- are upregulated by cocaine exposure. The molecular adapta- selective) to examine the effect of cocaine exposure on the tion of k2 receptor numbers may play a role in the motivational distribution and density of k2 receptors in autopsy studies of incentive associated with episodes of binge cocaine use and in human cocaine fatalities. The selective labeling of the k2 recep- the dysphoria that follows abrupt cocaine withdrawal. tor subtype was demonstrated by competition binding studies, Key words: cocaine; human brain; k opioid receptor; IOXY; which gave a pharmacological signature (IOXY $ (1)- delirium; dopamine Cocaine dependence results from the dysregulation of a number partial m-agonist/k antagonist buprenorphine reduces cocaine of distinct yet interacting neurochemical systems that act in con- self-administration by rhesus monkeys (Mello et al., 1993) and cert (Nestler et al., 1993). Cocaine enhances dopamine (DA) prevents the reinstatement of cocaine-reinforced responding in neurotransmission by interacting with the DA transporter and rats (Comer et al., 1993). Furthermore, buprenorphine reduces inhibiting the clearance of extracellular DA (Ritz et al., 1987; the use of cocaine in dual cocaine- and opiate-dependent men Reith et al., 1989; Kuhar et al., 1991). Mesolimbic DA neuro- (Mello and Mendelson, 1995). transmission is modulated by endogenous opioids that act at m The potent effects of k agonists on cocaine administration and k receptors to regulate DA release in the striatal reward suggest that k receptors may be a useful molecular target for the centers (DiChiara and Imperato, 1988; Spanagel et al., 1990, development of pharmacotherapies for cocaine dependence. 1992). Recent studies in animals have provided evidence for a However, drug development has been hindered by reports that in role of the k opioidergic system in the behavioral effects of humans, administration of k agonists elicits both aversive and cocaine (Shippenberg et al., 1996). k agonists inhibit cocaine psychotomimetic actions (Kumor et al., 1986; Pfeiffer et al., 1986; self-administration (Shippenberg et al., 1992; Glick et al., 1995), Herz, 1990). The recent identification of three subtypes of k cocaine-induced place preference (Suzuki et al., 1992; Heidbre- receptors with distinct pharmacological and molecular properties der et al., 1993), and the development of sensitization to the (Pfeiffer et al., 1982; Clark et al., 1989; Nishi et al., 1993; Wolle- behavioral effects of cocaine (Shippenberg and Heidbreder, 1994; mann et al., 1993; Raynor et al., 1994; Rothman, 1994; Pan et al., Heidbreder et al., 1995; Shippenberg et al., 1996). The mixed 1995; Simonin et al., 1995) has lead to the hypothesis that differ- ent k receptor subtypes may mediate distinct actions of k agonists Received April 1, 1997; revised Aug. 5, 1997; accepted Aug. 11, 1997. (Herz, 1990; Rothman et al., 1990; Ni et al., 1993, 1995; Rothman, This study was supported by United States Public Health Service Grant DA-06227 1994). The endogenous k agonist dynorphin A demonstrates (D.C.M.) and the Intramural Research Program of the National Institute on Drug Abuse. We thank Dr. Dorita Matecka for custom synthesizing BIT, FIT, and IOXY. 10-fold higher potency for binding to the k1 receptor (Simonin et We thank Margaret Basile and Qinjie Ouyang for their expert technical assistance. al., 1995) as compared with the k2 receptor (Ni et al., 1993, 1995), Correspondence should be addressed to Dr. Deborah C. Mash, Department of whereas truncated fragments of dynorphin A (i.e., dynorphin Neurology (D4-5), University of Miami School of Medicine, 1501 N.W. 9th Avenue, 1–11 Miami, FL 33136. and dynorphin1–13) exhibit higher potencies for binding to the k2 Copyright © 1997 Society for Neuroscience 0270-6474/97/178225-09$05.00/0 receptor over the k1 receptor (Nishi et al., 1993; Webster et al., • 8226 J. Neurosci., November 1, 1997, 17(21):8225–8233 Staley et al. k2 Opioid Receptors in Cocaine Dependence 1993). The molecular characterization of k receptor subtypes captopril). Cold saturation analysis was conducted by incubating mem- suggests that it may be possible to develop nondysphoric k- branes with increasing concentrations of unlabeled IOXY in the pres- ence of a fixed concentration of [ 125I]IOXY (0.04 nM) for 4 hr at 4°C. selective drugs as anti-cocaine medications. The pharmacological specificity of [ 125I]IOXY binding was determined The functional significance of each of the k receptor subtypes in by evaluating the potency of various opioid-like drugs in competition the CNS and their relevance to cocaine dependence is not under- binding assays. Nonspecific binding was defined using 10 mM naloxone. stood. Most studies have examined the effects of either nonselective Excess radioligand was separated from the bound radioligand using a or k -selective agonists on the behavioral effects of cocaine. The Brandel Cell Harvester. 1 In vitro autoradiography. Half-hemisphere slide-mounted sections of lack of highly selective ligands for the k2 and k3 receptor subtypes brain were prepared from cryopreserved neuropathological specimens. has limited the analysis of the precise role of these subtypes in From each coronal block, a series of adjacent cryostat sections were cocaine dependence. At present, the best available method to processed for [ 125I]IOXY autoradiography and for acetylcholinesterase measure k receptors is by using nonselective opioid radioligands histochemistry and Nissl substance to define cytoarchitectonic bound- 2 aries. For [ 125I]IOXY autoradiography, tissue sections were equilibrated in the presence of drugs to occlude binding of the radioligand at in 10 mM potassium phosphate, pH 7.4, at 4°C before tissue sections were defined opioid receptor sites. k2 receptors were originally identified treated with the site-directed acylating agents BIT (1 mM) and FIT (1 3 as high-affinity [ H]bremazocine binding sites in the presence of mM)in50mM potassium phosphate, pH 7.4, 100 mM NaCl to occlude drugs that occluded binding to the k , m, and d receptors (Webster binding to the m and d receptors, respectively. Slide-mounted brain tissue 1 125 et al., 1993). Recently, the k receptor has been characterized in rat sections were washed and incubated with [ I]IOXY (30 pM) in assay 2 buffer containing protease inhibitors at 4°C for 2–3 hr. Nonspecific brain using the opioid antagonist 6 b-[125iodo]-3,14-dihydroxy-17- binding was determined in the presence of 10 mM naloxone. At the end 125 cyclopropylmethyl-4,5 a-epoxymorphinan ([ I]IOXY) in the of the incubation, tissue sections were washed in two changes of ice-cold presence of m- and d-selective drug occluders (Ni et al., 1993, 1995). 10 mM Tris HCl, pH 7.4, and dried under a cool stream of air. Autora- The present study used this approach to visualize the distribution diograms were prepared by apposing the slide-mounted tissue sections along with co-placed iodine standards to Hyperfilm for 40–48 hr at of k2 receptors in the human brain for the first time. The effect of 125 280°C. cocaine exposure on the regulation of [ I]IOXY binding to the Data analysis. For analysis of ligand binding data, binding constants k2 receptor was evaluated in subgroups of cocaine overdose victims were derived from
Load more

Recommended publications
  • INVESTIGATION of NATURAL PRODUCT SCAFFOLDS for the DEVELOPMENT of OPIOID RECEPTOR LIGANDS by Katherine M
    INVESTIGATION OF NATURAL PRODUCT SCAFFOLDS FOR THE DEVELOPMENT OF OPIOID RECEPTOR LIGANDS By Katherine M. Prevatt-Smith 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 Doctor of Philosophy. _________________________________ Chairperson: Dr. Thomas E. Prisinzano _________________________________ Dr. Brian S. J. Blagg _________________________________ Dr. Michael F. Rafferty _________________________________ Dr. Paul R. Hanson _________________________________ Dr. Susan M. Lunte Date Defended: July 18, 2012 The Dissertation Committee for Katherine M. Prevatt-Smith certifies that this is the approved version of the following dissertation: INVESTIGATION OF NATURAL PRODUCT SCAFFOLDS FOR THE DEVELOPMENT OF OPIOID RECEPTOR LIGANDS _________________________________ Chairperson: Dr. Thomas E. Prisinzano Date approved: July 18, 2012 ii ABSTRACT Kappa opioid (KOP) receptors have been suggested as an alternative target to the mu opioid (MOP) receptor for the treatment of pain because KOP activation is associated with fewer negative side-effects (respiratory depression, constipation, tolerance, and dependence). The KOP receptor has also been implicated in several abuse-related effects in the central nervous system (CNS). KOP ligands have been investigated as pharmacotherapies for drug abuse; KOP agonists have been shown to modulate dopamine concentrations in the CNS as well as attenuate the self-administration of cocaine in a variety of species, and KOP antagonists have potential in the treatment of relapse. One drawback of current opioid ligand investigation is that many compounds are based on the morphine scaffold and thus have similar properties, both positive and negative, to the parent molecule. Thus there is increasing need to discover new chemical scaffolds with opioid receptor activity.
    [Show full text]
  • 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.
    [Show full text]
  • Oral Drug Delivery System Comprising High Viscosity
    (19) & (11) EP 1 575 569 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 9/52 (2006.01) 29.09.2010 Bulletin 2010/39 (86) International application number: (21) Application number: 03799943.0 PCT/US2003/040156 (22) Date of filing: 15.12.2003 (87) International publication number: WO 2004/054542 (01.07.2004 Gazette 2004/27) (54) ORAL DRUG DELIVERY SYSTEM COMPRISING HIGH VISCOSITY LIQUID CARRIER MATERIALS ORALE DARREICHUNGSFORM MIT FLÜSSIGEN HOCHVISKOSEN TRÄGERSYSTEMEN FORME D’ADMINISTRATION ORALE DE MEDICAMENTS COMPRENANT UN VEHICULE LIQUIDE DE HAUTE VISCOSITE (84) Designated Contracting States: • GIBSON, John, W. AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Sprinville, AL 35146 (US) HU IE IT LI LU MC NL PT RO SE SI SK TR • MIDDLETON, John, C. Birmingham, AL 35244 (US) (30) Priority: 13.12.2002 US 433116 P 04.11.2003 US 517464 P (74) Representative: Woods, Geoffrey Corlett J.A. Kemp & Co. (43) Date of publication of application: 14 South Square 21.09.2005 Bulletin 2005/38 Gray’s Inn London (60) Divisional application: WC1R 5JJ (GB) 10003425.5 / 2 218 448 (56) References cited: (73) Proprietor: Durect Corporation GB-A- 2 238 478 US-A- 5 266 331 Cupertino, CA 95014-4166 (US) US-B1- 6 413 536 (72) Inventors: • SULLIVANS A ET AL: "Sustained release of orally • YUM, Su, Il administered active using SABER(R) delivery Los Altos, CA 94024 (US) system incorporated into soft gelatin capsules" • SCHOENHARD, Grant PROCEEDINGS OF THE CONTROLLED San Carlos, CA 94070 (US) RELEASE SOCIETY 1998 UNITED STATES, no.
    [Show full text]
  • 1 Opioid Receptor
    Neuron, Vol. 11, 903-913, November, 1993, Copyright 0 1993 by Cell Press Cloning and Pharmacological Characterization of a Rat ~1Op ioid Receptor Robert C. Thompson, Alfred Mansour, Huda Akil, cortex, and have been shown to bind enkephalin-like and Stanley 1. Watson peptides (Mansour et al., 1988; Wood, 1988). 6 recep- Mental Health Research Institute tors are also thought to modulate several hormonal University of Michigan systems and to mediate analgesia. Ann Arbor, Michigan 48109-0720 The p receptors represent the third member of the opioid receptor family.These receptors bind morphine- like drugs and several endogenous opioid peptides, Summary including P-endorphin (derived from proopiomelano- cortin) and several members of both the enkephalin We have isolated a rat cDNA clone that displays 75% and the dynorphin opioid peptide families. These re- amino acid homology with the mouse 6 and rat K opioid ceptors have been localized in many regions of the receptors. The cDNA (designated pRMuR-12) encodes CNS, including the striatum (striatal patches), thalamus, a protein of 398 amino acids comprising, in part, seven nucleus tractus solitarius, and spinal cord (Mansour hydrophobic domains similar to those described for other et al., 1987; McLean et al., 1986; Temple and Zukin, 1987; C protein-linked receptors. Data from binding assays Wood, 1988; Mansour and Watson, 1993). p receptors conducted with COS-1 cells transiently transfected with appear to mediate the opiate phenomena classically a CMV mammalian expression vector containing the full associated with morphine and heroin administration, coding region of pRMuR-12 demonstrated p receptor including analgesia, opiate dependence, cardiovascu- selectivity.
    [Show full text]
  • CNS Drug Reviews Vol
    CNS Drug Reviews Vol. 11, No. 2, pp. 195–212 © 2005 Neva Press, Branford, Connecticut Bremazocine: A ê-Opioid Agonist with Potent Analgesic and Other Pharmacologic Properties Juanita Dortch-Carnes1 and David E. Potter2 1Department of Pharmacology/Toxicology, Morehouse School of Medicine, Atlanta, GA, USA; 2Department of Ophthalmology, Storm Eye Institute, Medical University of South Carolina, Charleston, SC, USA Keywords: Analgesia — Bremazocine — Diuresis — Dysphoria — ê-Opioid agonists — Ocu- lar hypotension — Respiration. ABSTRACT Bremazocine is a ê-opioid receptor agonist with potent analgesic and diuretic activities. As an analgesic it is three- to four-times more potent than morphine, as determined in both hot plate and tail flick tests. Bremazocine and other benzomorphan analogs were synthe- sized in an effort to produce opiates with greater ê-opioid receptor selectivity and with minimal morphine-like side effects. Unlike morphine bremazocine is devoid of physical and psychological dependence liability in animal models and produces little or no respi- ratory depression. While bremazocine does not produce the characteristic euphoria asso- ciated with morphine and its abuse, it has been shown to induce dysphoria, a property that limits its clinical usefulness. Similarly to morphine, repeated administration of bremazo- cine leads to tolerance to its analgesic effect. It has been demonstrated that the marked di- uretic effect of bremazocine is mediated primarily by the central nervous system. Because of its psychotomimetic side effects (disturbance in the perception of space and time, abnormal visual experience, disturbance in body image perception, de-personaliza- tion, de-realization and loss of self control) bremazocine has limited potential as a clinical analgesic.
    [Show full text]
  • NIDA Drug Supply Program Catalog, 25Th Edition
    RESEARCH RESOURCES DRUG SUPPLY PROGRAM CATALOG 25TH EDITION MAY 2016 CHEMISTRY AND PHARMACEUTICS BRANCH DIVISION OF THERAPEUTICS AND MEDICAL CONSEQUENCES NATIONAL INSTITUTE ON DRUG ABUSE NATIONAL INSTITUTES OF HEALTH DEPARTMENT OF HEALTH AND HUMAN SERVICES 6001 EXECUTIVE BOULEVARD ROCKVILLE, MARYLAND 20852 160524 On the cover: CPK rendering of nalfurafine. TABLE OF CONTENTS A. Introduction ................................................................................................1 B. NIDA Drug Supply Program (DSP) Ordering Guidelines ..........................3 C. Drug Request Checklist .............................................................................8 D. Sample DEA Order Form 222 ....................................................................9 E. Supply & Analysis of Standard Solutions of Δ9-THC ..............................10 F. Alternate Sources for Peptides ...............................................................11 G. Instructions for Analytical Services .........................................................12 H. X-Ray Diffraction Analysis of Compounds .............................................13 I. Nicotine Research Cigarettes Drug Supply Program .............................16 J. Ordering Guidelines for Nicotine Research Cigarettes (NRCs)..............18 K. Ordering Guidelines for Marijuana and Marijuana Cigarettes ................21 L. Important Addresses, Telephone & Fax Numbers ..................................24 M. Available Drugs, Compounds, and Dosage Forms ..............................25
    [Show full text]
  • Dextrorphan Binds to Opioid Receptors in Guinea-Pig Brain Membranes And
    Proc. Natl. Acad. Sci. USA Vol. 87, pp. 1629-1632, March 1990 Pharmacology Dextrorphan binds to opioid receptors in guinea-pig brain membranes and is an antagonist at opioid receptors in myenteric plexus (binding/guinea-pig ileum/levorphanol/stereoselectivity) AVRAM GOLDSTEIN AND ASHA NAIDU Department of Pharmacology, Stanford University, Stanford, CA 94305 Contributed by Avram Goldstein, December 11, 1989 ABSTRACT Dextrorphan (+)-tartrate, purified by re- LaRoche); [D-Ala,MePhe4,Gly-ol5]enkephalin (DAGO; Pe- peated crystallization to remove all traces of the enantiomer ninsula Laboratories) (2); trans-3,4-dichloro-N-methyl- levorphanol, binds to IL, 6, and K sites on guinea-pig brain N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide methane- membranes with lower affinities (by a factor of400-3200) than sulfonate (U50,488; Upjohn) (3); (-)-naloxone hydrochloride levorphanol. In the guinea-pig ileum myenteric plexus longi- (NAL; Endo Laboratories, New York); normorphine hydro- tudinal muscle preparation (GPI), dextrorphan, at 100-200 chloride (NOR) and (+)-naloxone hydrochloride (National ,uM, inhibits the electrically stimulated twitch, but this action Institute on Drug Abuse); N-methyl-D-aspartic acid (NMDA), is not blocked or reversed by naloxone; both (+)- and (-)- aminophosphonovalerate, norepinephrine (levarterenol), at- naloxone produce similar non-opioid twitch inhibition at com- ropine, and eserine (physostigmine) (Sigma). parable concentrations. At 10-20 jaM, dextrorphan' blocks and Preparation ofDEXp. [3H]LEV (Ro 1-5431/701, Hoffmann- reverses the twitch inhibition due to ,u and KWagonists, but the LaRoche; 17.4 Ci/mmol; 1 Ci = 37 GBq) was purified' by blockade can be overcome only partially by increasing the preparative reversed-phase HPLC (Waters, C18 AgBondaPak, agonist concentration.
    [Show full text]
  • Evaluation of Biased and Balanced Salvinorin a Analogs in Preclinical Models of Pain
    fnins-14-00765 July 18, 2020 Time: 20:26 # 1 ORIGINAL RESEARCH published: 21 July 2020 doi: 10.3389/fnins.2020.00765 Evaluation of Biased and Balanced Salvinorin A Analogs in Preclinical Models of Pain Kelly F. Paton1, Andrew Biggerstaff1, Sophia Kaska2, Rachel S. Crowley3, Anne C. La Flamme1,4, Thomas E. Prisinzano2,3 and Bronwyn M. Kivell1* 1 School of Biological Sciences, Centre for Biodiscovery, Faculty of Science, Victoria University of Wellington, Wellington, New Zealand, 2 Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, United States, 3 Department of Medicinal Chemistry, School of Pharmacy, The University of Kansas, Lawrence, KS, United States, 4 Malaghan Institute of Medical Research, Wellington, New Zealand In the search for safer, non-addictive analgesics, kappa opioid receptor (KOPr) agonists are a potential target, as unlike mu-opioid analgesics, they do not have abuse potential. Salvinorin A (SalA) is a potent and selective KOPr agonist, however, clinical utility is limited by the short duration of action and aversive side effects. Biasing KOPr signaling toward G-protein activation has been highlighted as a key cellular mechanism to reduce the side effects of KOPr agonists. The present study investigated KOPr signaling bias and the acute antinociceptive effects and side effects of two novel analogs of SalA, Edited by: 16-Bromo SalA and 16-Ethynyl SalA. 16-Bromo SalA showed G-protein signaling bias, Dominique Massotte, whereas 16-Ethynyl SalA displayed balanced signaling properties. In the dose-response Université de Strasbourg, France tail-withdrawal assay, SalA, 16-Ethynyl SalA and 16-Bromo SalA were more potent than Reviewed by: Mariana Spetea, the traditional KOPr agonist U50,488, and 16-Ethynyl SalA was more efficacious.
    [Show full text]
  • Long-Term Visceral Hypersensitivity Following Induction of Chemical
    Research Article ISSN: 2574 -1241 DOI: 10.26717/BJSTR.2020.30.005024 Long-Term Visceral Hypersensitivity Following Induction of Chemical Colitis is Primarily Reduced via Kappa Opiate Pathways - A Comparative Study of Different Opioidergic Subtypes D Engel1,2, M Stutz1,2, JC Miller1,2, B Flogerzi1,2, L Tovar1,2, Scheurer U1,2 and Gschossmann JM*1,2 1Department of Visceral Surgery and Medicine, Inselspital, Switzerland 2Department of Clinical Research, Inselspital, Switzerland *Corresponding author: Juergen MGschossmann, Klinikum Forchheim, Department of Internal Medicine, Krankenhausstrasse 10, D-91301 Forchheim, Germany ARTICLE INFO ABSTRACT Received: September 25, 2020 Background/Aims: Transient gastrointestinal infections frequently precede functional bowel disorders with altered visceral sensory function. The aim of our study Published: October 02, 2020 was a) to demonstrate the long-term effect of a chemically induced colitis on visceral sensory function in response to phasic colorectal distensions (CRD) and b) to analyze the impact of different opiate receptor agonists (ORA) and the NMDA antagonist ketamine on Citation: D Engel, M Stutz, JC Miller, B modulation of visceral hypersensitivity following chemical colitis in a rat model. Flogerzi, L Tovar, Scheurer U, Gschoss- mann JM. Long-Term Visceral Hypersen- Methods: In forty male Lewis rats, 6 weeks after induction of trinitrobenzene sulfonic sitivity Following Induction of Chemical acid (TNB) colitis (colitis group) versus saline (control group), electromyographic Colitis is Primarily Reduced via Kappa recordings of CRD were performed. Different ORA and/or ketamine were administered Opiate Pathways - A Comparative Study intraperitoneally. of Different Opioidergic Subtypes. Bi- Results: The chemically induced colitis was followed by persistent visceral omed J Sci & Tech Res 30(5)-2020.
    [Show full text]
  • Interactions of the Opioid and Cannabinoid Systems in Reward: Insights from Knockout Studies
    REVIEW ARTICLE published: 05 February 2015 doi: 10.3389/fphar.2015.00006 Interactions of the opioid and cannabinoid systems in reward: Insights from knockout studies Katia Befort* CNRS, Laboratoire de Neurosciences Cognitives et Adaptatives – UMR7364, Faculté de Psychologie, Neuropôle de Strasbourg – Université de Strasbourg, Strasbourg, France Edited by: The opioid system consists of three receptors, mu, delta, and kappa, which are Dominique Massotte, Institut des activated by endogenous opioid peptides (enkephalins, endorphins, and dynorphins). The Neurosciences Cellulaires et Intégratives, France endogenous cannabinoid system comprises lipid neuromodulators (endocannabinoids), enzymes for their synthesis and their degradation and two well-characterized receptors, Reviewed by: Fernando Berrendero, Universitat cannabinoid receptors CB1 and CB2. These systems play a major role in the control of Pompeu Fabra, Spain pain as well as in mood regulation, reward processing and the development of addiction. Krisztina Monory, University Medical Both opioid and cannabinoid receptors are coupled to G proteins and are expressed Centre of the Johannes Gutenberg University, Germany throughout the brain reinforcement circuitry. Extending classical pharmacology, research using genetically modified mice has provided important progress in the identification of the *Correspondence: Katia Befort, CNRS, Laboratoire de specific contribution of each component of these endogenous systems in vivo on reward Neurosciences Cognitives et process. This review will summarize available genetic tools and our present knowledge on Adaptatives – UMR7364, Faculté de the consequences of gene knockout on reinforced behaviors in both systems, with a focus Psychologie, Neuropôle de Strasbourg – Université de on their potential interactions. A better understanding of opioid–cannabinoid interactions Strasbourg, 12, rue Goethe, F -67000 may provide novel strategies for therapies in addicted individuals.
    [Show full text]
  • The Kappa Opioid Agonist, Salvinorin A, Attenuates Locomotor Effects of Morphine but Not Morphine-Induced Conditioned Place Preference
    Western Michigan University ScholarWorks at WMU Master's Theses Graduate College 6-2012 The Kappa Opioid Agonist, Salvinorin A, Attenuates Locomotor Effects of Morphine but not Morphine-Induced Conditioned Place Preference Stacy Dianne Engebretson Follow this and additional works at: https://scholarworks.wmich.edu/masters_theses Part of the Psychology Commons Recommended Citation Engebretson, Stacy Dianne, "The Kappa Opioid Agonist, Salvinorin A, Attenuates Locomotor Effects of Morphine but not Morphine-Induced Conditioned Place Preference" (2012). Master's Theses. 67. https://scholarworks.wmich.edu/masters_theses/67 This Masters Thesis-Open Access is brought to you for free and open access by the Graduate College at ScholarWorks at WMU. It has been accepted for inclusion in Master's Theses by an authorized administrator of ScholarWorks at WMU. For more information, please contact [email protected]. THE KAPPA OPIOID AGONIST, SALVINORIN A, ATTENUATES LOCOMOTOR EFFECTS OF MORPHINE BUT NOT MORPHINE-INDUCED CONDITIONED PLACE PREFERENCE by Stacy Dianne Engebretson A Thesis Submitted to the Faculty of the Graduate College in partial fulfillment of the requirements for the Degree of Master of Arts Department of Psychology Advisor: Lisa E. Baker, Ph. D. Western Michigan University Kalamazoo, Michigan June 2012 THE GRADUATE COLLEGE WESTERN MICHIGAN UNIVERSITY KALAMAZOO, MICHIGAN Date May 23, 2012 WE HEREBY APPROVE THE THESIS SUBMITTED BY Stacy Dianne Engebretson ENTITLED The Kappa Opioid Agonist, Salvinorin A, Attenuates Locomotor Effects of Morphine but Not Morphine-Induced Conditioned Place Preference. AS PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF Master of Arts Psychology (Department) Thesis Committee Behavior Analysis ®4o^Q& (Program) Alan D. Poling, Ph.! Thesis Committee Memf APPROVED s$AM>sr\ Date UlUL U\l Dean of>f The Graduate College THE KAPPA OPIOID AGONIST, SALVINORIN A, ATTENUATES LOCOMOTOR EFFECTS OF MORPHINE BUT NOT MORPHINE-INDUCED CONDITIONED PLACE PREFERENCE Stacy Dianne Engebretson, M.A.
    [Show full text]
  • Chemistry of Compounds Journal Benzomorphan Skeleton As Scaffold for Analgesic, Antiviral and Antitumoral Drugs
    www.verizonaonlinepublishing.com Vol: 1, Issue: 1 Chemistry of Compounds Journal Benzomorphan Skeleton as Scaffold for Analgesic, Antiviral and Antitumoral drugs Rita Turnaturi* and Lorella Pasquinucci Department of Drug Sciences, Medicinal Chemistry Section, University of Catania *Corresponding author: Rita Turnaturi, Department of Drug Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy; Tel: +39-0957384017; E mail: [email protected] Article Type: Short Communication, Submission Date: 26 August 2016, Accepted Date: 19 September 2016, Published Date: 27 October 2016. Citation: Rita Turnaturi and Lorella Pasquinucci (2016) Benzomorphan Skeleton as Scaffold for Analgesic, Antiviral and Antitumoral drugs. Chemi.Compol. J 1(1): 6-7. Copyright: © 2016 Rita Turnaturi and Lorella Pasquinucci. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract analgesic in phase II clinical trials that acts as a partial agonist of the mu and delta opioid receptors (MOR and DOR). Similarly, Benzomorphan core is a versatile structure. In fact, it represented Bremazocine[4] (Figure 2b) is a kappa opioid receptor (KOR) the skeleton of drugs with different mechanism of action, from agonist related to pentazocine and possesses potent and long- opioid to σ1 receptor, from antiviral to antiproliferative. lasting analgesic and diuretic effects. Alazocine ((-)-SKF-10,047, Based upon these considerations, the design, synthesis and bio- Figure 2c) [5] is the first drug discovered to act at sigma1 (σ1) logical evaluation of benzomorphan-based compounds as puta- receptor. Crobenetine[6] (Figure 2d) is a potent, selective and tive antiviral and/or antitumoral drug candidates could represent highly use-dependent Na+ channel blocker.
    [Show full text]