DOCSLIB.ORG

Anti-Inflammatory Lipoxin A4 Is an Endogenous Allosteric Enhancer Of

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Anti-Inflammatory Lipoxin A4 Is an Endogenous Allosteric Enhancer Of Correction PHARMACOLOGY Correction for “Anti-inflammatory lipoxin A4 is an endogenous allosteric enhancer of CB1 cannabinoid receptor,” by Fabricio A. Pamplona, Juliano Ferreira, Octávio Menezes de Lima, Jr., Filipe Silveira Duarte, Allisson Freire Bento, Stefânia Forner, Jardel G. Villarinho, Luigi Bellochio, Carsten T. Wotjak, Raissa Lerner, Krisztina Monory, Beat Lutz, Claudio Canetti, Isabelle Matias, João Batista Calixto, Giovanni Marsicano, Marilia Z. P. Guimarães, and Reinaldo N. Takahashi, which appeared in issue 51, December 18, 2012, of Proc Natl Acad Sci USA (109:21134–21139; first published November 12, 2012; 10.1073/ pnas.1202906109). The authors note that the author name Luigi Bellochio should instead appear as Luigi Bellocchio. The corrected author line appears below. The online version has been corrected. Fabricio A. Pamplona, Juliano Ferreira, Octávio Menezes de Lima, Jr., Filipe Silveira Duarte, Allisson Freire Bento, Stefânia Forner, Jardel G. Villarinho, Luigi Bellocchio, Carsten T. Wotjak, Raissa Lerner, Krisztina Monory, Beat Lutz, Claudio Canetti, Isabelle Matias, João Batista Calixto, Giovanni Marsicano, Marilia Z. P. Guimarães, and Reinaldo N. Takahashi www.pnas.org/cgi/doi/10.1073/pnas.1221727110 CORRECTION www.pnas.org PNAS | January 22, 2013 | vol. 110 | no. 4 | 1561 Downloaded by guest on September 26, 2021 Anti-inflammatory lipoxin A4 is an endogenous allosteric enhancer of CB1 cannabinoid receptor Fabricio A. Pamplonaa,b,1, Juliano Ferreirac, Octávio Menezes de Lima, Jr.a, Filipe Silveira Duartea, Allisson Freire Bentoa, Stefânia Fornera, Jardel G. Villarinhoc, Luigi Bellocchiod,e, Carsten T. Wotjakf, Raissa Lernerg, Krisztina Monoryg, Beat Lutzg, Claudio Canettih, Isabelle Matiasd,e, João Batista Calixtoa, Giovanni Marsicanod,e,2, Marilia Z. P. Guimarãesi,2, and Reinaldo N. Takahashia,1,2 aLaboratory of Psychopharmacology, Department of Pharmacology, Universidade Federal de Santa Catarina, 88049-900, Florianópolis, Brazil; bD’Or Institute for Research and Education, 22281-100, Rio de Janeiro, Brazil; cDepartment of Chemistry, Universidade Federal de Santa Maria, 97105-900, Santa Maria, Brazil; dInstitut National de la Santé et de la Recherche Médicale U862, NeuroCentre Magendie, Endocannabinoids and Neuroadaptation, 33077 Bordeaux, France; eU862 NeuroCentre Magendie, Group Endocannabinoids and Neuroadaptation, 33077 Bordeaux, France; fLaboratory of Neuroplasticity, Max Planck Institute of Psychiatry, D-80804 Munich, Germany; gInstitute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg- University, D-55099 Mainz, Germany; hInstituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, Brazil; and iInstituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-599, Rio de Janeiro, Brazil Edited by Leslie Lars Iversen, University of Oxford, Oxford, United Kingdom, and approved October 16, 2012 (received for review February 27, 2012) Allosteric modulation of G-protein–coupled receptors represents a Two synthetic compounds, Org27596 and Org29647, enhance the key goal of current pharmacology. In particular, endogenous alloste- affinity and reduce the efficacy of CB1 agonists, suggesting the ric modulators might represent important targets of interventions existence of an allosteric binding site at CB1 receptor (9). However, aimed at maximizing therapeutic efficacy and reducing side effects the existence of endogenous allosteric cannabinoid modulators fl of drugs. Here we show that the anti-in ammatory lipid lipoxin A4 has not yet been proved. is an endogenous allosteric enhancer of the CB1 cannabinoid receptor. Synthetic and metabolic pathways of eicosanoids impact endo- Lipoxin A4 was detected in brain tissues, did not compete for the cannabinoid levels, suggesting functional relationships among 3 orthosteric binding site of the CB1 receptor (vs. H-SR141716A), and endocannabinoids, prostaglandins (10), and lipoxins (11). Lipoxin did not alter endocannabinoid metabolism (as opposed to URB597 A4 (LXA4), the most studied endogenous lipoxin (12), is largely and MAFP), but it enhanced affinity of anandamide at the CB1 re- involved in immune system regulation and is linked to resolution ceptor, thereby potentiating the effects of this endocannabinoid of inflammation (13). The metabotropic ALX receptor (also both in vitro and in vivo. In addition, lipoxin A4 displayed a CB1 called FPRL-1) is responsible for the immunological effects of receptor-dependent protective effect against β-amyloid (1–40)- LXA4 and is expressed in peripheral organs, but has negligible induced spatial memory impairment in mice. The discovery of lip- occurrence in the central nervous system (CNS) (14). Neverthe- oxins as a class of endogenous allosteric modulators of CB1 receptors less, LXA4 is released in brain tissues during ischemia (15), sug- may foster the therapeutic exploitation of the endocannabinoid sys- gesting the presence of non-ALX receptor targets in the brain. tem, in particular for the treatment of neurodegenerative disorders. Brain effects of LXA4 include modulation of slow wave sleep (16), neuronal signaling (via PKCγ) (17, 18), and plasticity (19) allosteric modulation | psychopharmacology | GPCR | inflammation | through unknown mechanisms. Interestingly, these effects are neuroprotection similar to those of the endocannabinoid AEA (20, 21). We previously showed that intracerebroventricular (i.c.v.) injections he endocannabinoid system, comprising metabotropic can- of the aspirin-triggered LXA4 (15-Epi-LXA4) induce cannabinoid- Tnabinoid receptors (CB1 and CB2), endogenous lipid ligands like catalepsy in mice, which was prevented by the CB1 antagonist (endocannabinoids), and enzymes responsible for their synthesis SR141716A and not by an ALX antagonist. Altogether, these and degradation, is a key regulator of neuronal function, being findings suggest that LXA could have CB receptor-dependent proposed as a therapeutic target for several diseases (1). Acti- 4 1 effects in the brain (22). Here we report that LXA4 not only vation of CB1 receptors reduces cAMP levels, inhibits voltage- 2+ + binds to CB1 receptors to exert cannabimimetic effects in the dependent Ca channels, and activates inward-rectifying K brain, but does so by allosterically enhancing AEA signaling. channels, resulting in reduced neuronal excitability and pre- This may have important implications for the therapeutic ex- synaptic inhibition of neurotransmitter release (1, 2). The effi- ploitation of the endocannabinoid system. cacy of endogenous CB1 agonists varies according to the nature of the molecule (3). The endocannabinoid anandamide (AEA) is Results considered a partial agonist, whereas 2-arachidonoylglycerol LXA4 Displays Cannabimimetic Effects in the Brain. The cannabinoid (2-AG) is a full agonist inducing maximal responses (4, 5). At “tetrad” represents a prototypic signature of cannabinoid effects least three other endocannabinoids are known (noladin ether, (23). Brain injection of LXA (1 pmol/5 μL, i.c.v.) induced the virodhamine, and N-arachidonoyl dopamine) (1, 2). Each endo- 4 cannabinoid has different affinities, efficacies, and sometimes distinct effects at the CB1 receptor, which could also be cell type- Author contributions: F.A.P., J.F., O.M.d.L., B.L., I.M., J.B.C., G.M., M.Z.P.G., and R.N.T. dependent (1, 2). Cannabinoids have many effects on laboratory designed research; F.A.P., J.F., F.S.D., A.F.B., S.F., J.G.V., L.B., R.L., K.M., I.M., and M.Z.P.G. animals, but the prominent ones are known as the cannabinoid performed research; C.T.W., B.L., and C.C. contributed new reagents/analytic tools; F.A.P. and tetrad: analgesia, catalepsy, hypolocomotion, and hypothermia. J.F. analyzed data; and F.A.P., G.M., and M.Z.P.G. wrote the paper. fl The selectivity of CB1 agonists may be explained by multiple The authors declare no con ict of interest. binding sites in the CB1 receptor (6), in agreement with the cur- This article is a PNAS Direct Submission. rent view of metabotropic receptors as dynamic macromolecules, See Commentary on page 20781. rather than mere on/off switches of a transduction system (7). 1To whom correspondence may be addressed. E-mail: [email protected] or Allosteric modulators bind to additional site(s) on the receptor [email protected]. influencing the affinity and/or efficacy of endogenous molecules 2G.M., M.Z.P.G., and R.N.T. contributed equally to this work. binding to the orthosteric or primary site (the orthosteric site is This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. defined as the binding site for known endogenous ligand) (8). 1073/pnas.1202906109/-/DCSupplemental. 21134–21139 | PNAS | December 18, 2012 | vol. 109 | no. 51 www.pnas.org/cgi/doi/10.1073/pnas.1202906109 B (Fig. 3A), but not the one of 2-AG (Fig. S3A)orsignificantly of A SEE COMMENTARY CP55940 (Fig. S4). LXA4 might potentiate the effect of AEA by inhibiting endocannabinoid degradation. However, LXA4 did not alter the activity of the main AEA-degrading enzyme fatty acid amide hydrolase (FAAH; Fig. 3B), nor of the main 2-AG– degrading enzyme monoacylglycerol lipase (Fig. S3B). Consis- tently, i.c.v. administration of LXA4 did not alter brain levels of AEA (Fig. 3C) or of 2-AG (Fig. S3C). The interaction between LXA4 and AEA was further confirmed in HEK cells transfected with mouse CB1 receptors. LXA4 increased the potency of AEA in decreasing forskolin (FSK)-induced cAMP levels by ∼386 times (EC50 AEA 1,547 nM
Load more

Recommended publications
  • Modulation of Central Endocannabinoid System Results in Gastric Mucosal Protection in the Rat
    Modulation of central endocannabinoid system results in gastric mucosal protection in the rat Tóth, V.E.1, Fehér, Á.1, Németh, J.2, Gyertyán, I.3, Zádori, Z.S.1, Gyires K.1 1 Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4., 1089 Budapest, Hungary; 2 Department of Pharmacology and Pharmacotherapy, University of Debrecen, Nagyerdei krt. 98., 4032 Debrecen, Hungary; 3 MTA-SE NAP B Cognitive Translational Behavioural Pharmacology Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvárad tér 4., 1089 Budapest, Hungary *Corresponding author: Klára Gyires Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvárad tér 4., 1089, Budapest, Hungary Phone: 36-1-210-4416, Fax: 36-1-210-4412 e-mail: [email protected] 1 Abstract Previous findings showed that inhibitors of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), degrading enzymes of anandamide (2-AEA) and 2- arachidonoylglycerol (2-AG), reduced the nonsteroidal anti-inflammatory drug-induced gastric lesions. The present study aimed to investigate: i./whether central or peripheral mechanism play a major role in the gastroprotective effect of inhibitors of FAAH, MAGL and AEA uptake, ii./ which peripheral mechanism(s) may be responsible for mucosal protective effect of FAAH, MAGL and uptake inhibitors. Methods: Gastric mucosal damage was induced by acidified ethanol. Gastric motility was measured in anesthetized rats. Catalepsy and the body temperature were also evaluated. Mucosal calcitonin gene- related peptide (CGRP), somatostatin concentrations and superoxide dismutase (SOD) activity were measured. The compounds were injected intraperitoneally (i.p.) or intracerebroventricularly (i.c.v.). Results: 1. URB 597, JZL184 (inhibitors of FAAH and MAGL) and AM 404 (inhibitor of AEA uptake) decreased the mucosal lesions significantly given either i.c.v.
    [Show full text]
  • Cannabinoids in the Pathophysiology of Skin Inflammation
    molecules Review Cannabinoids in the Pathophysiology of Skin Inflammation Cristian Scheau 1 , Ioana Anca Badarau 1, Livia-Gratiela Mihai 1, Andreea-Elena Scheau 2, Daniel Octavian Costache 3, Carolina Constantin 4,5, Daniela Calina 6 , Constantin Caruntu 1,7,*, Raluca Simona Costache 8,* and Ana Caruntu 9,10 1 Department of Physiology, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; [email protected] (C.S.); [email protected] (I.A.B.); [email protected] (L.-G.M.) 2 Department of Radiology and Medical Imaging, Fundeni Clinical Institute, 022328 Bucharest, Romania; [email protected] 3 Department of Dermatology, “Carol Davila” Central Military Emergency Hospital, 010825 Bucharest, Romania; [email protected] 4 Immunology Department, ”Victor Babes” National Institute of Pathology, 050096 Bucharest, Romania; [email protected] 5 Department of Pathology, Colentina University Hospital, 020125 Bucharest, Romania 6 Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; [email protected] 7 Department of Dermatology, “Prof. N. Paulescu” National Institute of Diabetes, Nutrition and Metabolic Diseases, 011233 Bucharest, Romania 8 Gastroenterology and Internal Medicine Clinic, Carol Davila University Central Emergency Military Hospital, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania 9 Department of Oral and Maxillofacial Surgery, “Carol Davila” Central Military Emergency Hospital, 010825 Bucharest, Romania; [email protected] 10 Faculty of Medicine, “Titu Maiorescu” University, 031593 Bucharest, Romania * Correspondence: [email protected] (C.C.); [email protected] (R.S.C.); Tel.: +40-745-086-978 (C.C.) Academic Editor: Eric J. Downer Received: 30 December 2019; Accepted: 2 February 2020; Published: 4 February 2020 Abstract: Cannabinoids are increasingly-used substances in the treatment of chronic pain, some neuropsychiatric disorders and more recently, skin disorders with an inflammatory component.
    [Show full text]
  • The Selective Reversible FAAH Inhibitor, SSR411298, Restores The
    www.nature.com/scientificreports OPEN The selective reversible FAAH inhibitor, SSR411298, restores the development of maladaptive Received: 22 September 2017 Accepted: 26 January 2018 behaviors to acute and chronic Published: xx xx xxxx stress in rodents Guy Griebel1, Jeanne Stemmelin2, Mati Lopez-Grancha3, Valérie Fauchey3, Franck Slowinski4, Philippe Pichat5, Gihad Dargazanli4, Ahmed Abouabdellah4, Caroline Cohen6 & Olivier E. Bergis7 Enhancing endogenous cannabinoid (eCB) signaling has been considered as a potential strategy for the treatment of stress-related conditions. Fatty acid amide hydrolase (FAAH) represents the primary degradation enzyme of the eCB anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). This study describes a potent reversible FAAH inhibitor, SSR411298. The drug acts as a selective inhibitor of FAAH, which potently increases hippocampal levels of AEA, OEA and PEA in mice. Despite elevating eCB levels, SSR411298 did not mimic the interoceptive state or produce the behavioral side-efects (memory defcit and motor impairment) evoked by direct-acting cannabinoids. When SSR411298 was tested in models of anxiety, it only exerted clear anxiolytic-like efects under highly aversive conditions following exposure to a traumatic event, such as in the mouse defense test battery and social defeat procedure. Results from experiments in models of depression showed that SSR411298 produced robust antidepressant-like activity in the rat forced-swimming test and in the mouse chronic mild stress model, restoring notably the development of inadequate coping responses to chronic stress. This preclinical profle positions SSR411298 as a promising drug candidate to treat diseases such as post-traumatic stress disorder, which involves the development of maladaptive behaviors. Te endocannabinoid (eCB) system is formed by two G protein-coupled receptors, CB1 and CB2, and their main transmitters, N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoyglycerol (2-AG)1.
    [Show full text]
  • Assessment of Anandamide's Pharmacological Effects in Mice Deficient of Both Fatty Acid Amide Hydrolase and Cannabinoid CB1 Receptors
    European Journal of Pharmacology 557 (2007) 44–48 www.elsevier.com/locate/ejphar Short communication Assessment of anandamide's pharmacological effects in mice deficient of both fatty acid amide hydrolase and cannabinoid CB1 receptors Laura E. Wise a, Christopher C. Shelton a, Benjamin F. Cravatt b, ⁎ Billy R. Martin a, Aron H. Lichtman a, a Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298-0613, United States b The Skaggs Institute for Chemical Biology and Departments of Cell Biology and Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd. La Jolla, CA 92037, United States Received 12 September 2006; received in revised form 2 November 2006; accepted 6 November 2006 Available online 10 November 2006 Abstract In the present study, we investigated whether anandamide produces its behavioral effects through a cannabinoid CB1 receptor mechanism of action. The behavioral effects of anandamide were evaluated in mice that lacked both fatty acid amide hydrolase (FAAH) and cannabinoid CB1 receptors (DKO) as compared to FAAH (−/−), cannabinoid CB1 (−/−), and wild type mice. Anandamide produced analgesia, catalepsy, and hypothermia in FAAH (−/−) mice, but failed to elicit any of these effects in the other three genotypes. In contrast, anandamide decreased locomotor behavior regardless of genotype, suggesting the involvement of multiple mechanisms of action, including its products of degradation. These findings indicate that the cannabinoid CB1 receptor is the predominant target mediating anandamide's behavioral effects. © 2006 Elsevier B.V. All rights reserved. Keywords: Cannabinoid CB1 receptor; FAAH [Fatty acid amide hydrolase]; N-arachidonoyl ethanolamine (anandamide); Pain; Analgesia; Marijuana 1.
    [Show full text]
  • The Handbook of Cannabis Therapeutics: from Bench to Bedside
    Handbook of Cannabis Therapeutics From Bench to Bedside 9780789030979 Handbook of Cannabis Therapeutics From Bench to Bedside Size: 212 x 152mm Spine size: 26 mm Color pages: Binding: Paperback THE HAWORTH PRESS® Haworth Series in Integrative Healing Ethan Russo Editor The Last Sorcerer: Echoes of the Rainforest by Ethan Russo Professionalism and Ethics in Complementary and Alternative Medicine by John Crellin and Fernando Ania Cannabis and Cannabinoids: Pharmacology, Toxicology, and Therapeutic Potential by Franjo Grotenhermen and Ethan Russo Modern Psychology and Ancient Wisdom: Psychological Healing Practices from the World’s Religious Traditions edited by Sharon G. Mijares Complementary and Alternative Medicine: Clinic Design by Robert A. Roush Herbal Voices: American Herbalism Through the Words of American Herbalists by Anne K. Dougherty The Healing Power of Chinese Herbs and Medicinal Recipes by Joseph P. Hou and Youyu Jin Alternative Therapies in the Treatment of Brain Injury and Neurobehavioral Disorders: A Practical Guide edited by Gregory J. Murrey Handbook of Cannabis Therapeutics: From Bench to Bedside edited by Ethan B. Russo and Franjo Grotenhermen Handbook of Cannabis Therapeutics From Bench to Bedside Ethan B. Russo, MD Franjo Grotenhermen, MD Editors Routledge Taylor &. Francis Croup NEW YORK AND LONDON First Published by The Haworth Press, Inc., 10 Alice Street, Binghamton, NY 13904-1580. Transferred to Digital Printing 2010 by Routledge 270 Madison Ave, New York NY 10016 2 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN For more information on this book or to order, visit http://www.haworthpress.com/store/product.asp?sku=5741 or call 1-800-HAWORTH (800-429-6784) in the United States and Canada or (607) 722-5857 outside the United States and Canada or contact [email protected] © 2006 by The Haworth Press, Inc.
    [Show full text]
  • Appendix-2Final.Pdf 663.7 KB
    North West ‘Through the Gate Substance Misuse Services’ Drug Testing Project Appendix 2 – Analytical methodologies Overview Urine samples were analysed using three methodologies. The first methodology (General Screen) was designed to cover a wide range of analytes (drugs) and was used for all analytes other than the synthetic cannabinoid receptor agonists (SCRAs). The analyte coverage included a broad range of commonly prescribed drugs including over the counter medications, commonly misused drugs and metabolites of many of the compounds too. This approach provided a very powerful drug screening tool to investigate drug use/misuse before and whilst in prison. The second methodology (SCRA Screen) was specifically designed for SCRAs and targets only those compounds. This was a very sensitive methodology with a method capability of sub 100pg/ml for over 600 SCRAs and their metabolites. Both methodologies utilised full scan high resolution accurate mass LCMS technologies that allowed a non-targeted approach to data acquisition and the ability to retrospectively review data. The non-targeted approach to data acquisition effectively means that the analyte coverage of the data acquisition was unlimited. The only limiting factors were related to the chemical nature of the analyte being looked for. The analyte must extract in the sample preparation process; it must chromatograph and it must ionise under the conditions used by the mass spectrometer interface. The final limiting factor was presence in the data processing database. The subsequent study of negative MDT samples across the North West and London and the South East used a GCMS methodology for anabolic steroids in addition to the General and SCRA screens.
    [Show full text]
  • The Endocannabinoid System and Harm Reduc on with Cannabis
    The Endocannabinoid System and Harm Reduc6on with Cannabis Gregory Gerdeman, PhD Mary Lynn Mathre, RN, MSN, CARN Cannabis is real medicine • Cannabis is safe medicine • Studying cannabis led to discovery of the Ethan Russo, MD ENDOCANNABINOID SYSTEM (ECS) • Cannabinoid receptors (acvated by THC) • Endogenous THC-like cannabinoid signaling molecules (endocannabinoids) • Endocannabinoid metabolic enzymes • ECS is a “master regulator” of human physiology Effects of cannabis in the brain are undeniably the root of human aOracGon and aversion – both – to this plant that has been culvated and ulized as medicine for longer than any historical record. A Gmeline of major discoveries in the research of cannabis and the cannabinoids 1964 – Gaoni and Mechoulam isolate Δ9-THC from hashish 1980’s – “Tetrad” test of cannabinoid effects is developed, and used to test syntheGc analogs. 1988 – CB1 cannabinoid receptor is idenGfied. 1992 – Anandamide is discovered as first endocannabinoid The focus of cannabis research in the 2nd half of the 20th century was not so even-handed. • How does marijuana make someone… • Stoned Led to … The • Lazy endocannabinoid • Addicted (including to other drugs) system • Violent!!! • Mentally impaired for life… brain damage model (THC as neurotoxin) • Insane (paranoid schizophrenia) Mainstream scienGfic concepGons of the endocannabinoid system are now well beyond the exclusive domain of drug abuse research … Endocannabinoid signaling as a synapGc circuit breaker in neurological disease István Katona & Tamás F Freund Nature Medicine,
    [Show full text]
  • Cannabinoid Hope for MND Potent Pot Linked to Psychosis
    Highlights from clinical trials on cannabis science RESEARCH ROUND-UP By Liam Drew SPASTICITY Cannabinoid hope for MND A clinical trial of a cannabi- noid oral spray that is used to treat people with multiple sclerosis (MS) suggests that the treatment could also ease the symptoms of motor neuron disease (MND). The treatment targets spasticity, a condition caused by the permanent contraction of muscles, which impedes a person’s movement. It is a prominent symptom of both MND and MS. In 2010, after a long history of people with MS using cannabis to self-medicate, a cannabis- based treatment to manage spasticity associated with MS was approved in the United Kingdom. Giancarlo Comi at Vita-Salute San Raffaele University in Milan, Italy, and his colleagues now suggest that this same cannabinoid preparation can ease spasticity in people with MND. decreased people’s reported psychosis — a condition in of strains containing less than In a double-blind, rand- pain levels. Future studies which a person’s perception of 10% THC. But using strains omized phase II trial, 30 people might more finely distinguish reality is distorted. that contained more than 10% received a placebo and 29 peo- the treatment’s efficacy in two The researchers surveyed THC made the probability of ple were given the cannabinoid forms of MND: amyotrophic 901 people with psychotic developing psychosis almost spray — a solution containing lateral sclerosis, in which spas- disorders, who had been five times higher than that of roughly equal amounts of tet- ticity varies in its prevalence admitted into psychiatric care non-users.
    [Show full text]
  • A Budding Source of Targets for Treating Inflammatory and Neuropathic Pain
    Clinical and Translational Science Institute Centers 1-1-2018 The Endogenous Cannabinoid System: A Budding Source of Targets for Treating Inflammatory and Neuropathic Pain Giulia Donvito Virginia Commonwealth University Sara R. Nass West Virginia University Jenny L. Wilkerson Virginia Commonwealth University Zachary A. Curry Virginia Commonwealth University Lesley D. Schurman Virginia Commonwealth University See next page for additional authors Follow this and additional works at: https://researchrepository.wvu.edu/ctsi Part of the Medicine and Health Sciences Commons Digital Commons Citation Donvito, Giulia; Nass, Sara R.; Wilkerson, Jenny L.; Curry, Zachary A.; Schurman, Lesley D.; Kinsey, Steven G.; and Lichtman, Aron H., "The Endogenous Cannabinoid System: A Budding Source of Targets for Treating Inflammatory and Neuropathic Pain" (2018). Clinical and Translational Science Institute. 717. https://researchrepository.wvu.edu/ctsi/717 This Article is brought to you for free and open access by the Centers at The Research Repository @ WVU. It has been accepted for inclusion in Clinical and Translational Science Institute by an authorized administrator of The Research Repository @ WVU. For more information, please contact [email protected]. Authors Giulia Donvito, Sara R. Nass, Jenny L. Wilkerson, Zachary A. Curry, Lesley D. Schurman, Steven G. Kinsey, and Aron H. Lichtman This article is available at The Research Repository @ WVU: https://researchrepository.wvu.edu/ctsi/717 Neuropsychopharmacology REVIEWS (2018) 43, 52–79 © 2018 American
    [Show full text]
  • Distinct Roles of the Endocannabinoids Anandamide and 2-Arachidonoylglycerol in Social Behavior and Emotionality at Different Developmental Ages in Rats
    European Neuropsychopharmacology (2015) 25, 1362–1374 www.elsevier.com/locate/euroneuro Distinct roles of the endocannabinoids anandamide and 2-arachidonoylglycerol in social behavior and emotionality at different developmental ages in rats Antonia Manducaa, Maria Morenab,c, Patrizia Campolongob, Michela Servadioa, Maura Palmeryb, Luigia Trabaced, Matthew N. Hillc, Louk J.M.J. Vanderschurene,f, Vincenzo Cuomob, Viviana Trezzaa,n aDepartment of Science, Section of Biomedical Sciences and Technologies, University “Roma Tre”, Rome, Italy bDepartment of Physiology and Pharmacology, Sapienza, University of Rome, Rome, Italy cHotchkiss Brain Institute, Departments of Cell Biology and Anatomy and Psychiatry, University of Calgary, Calgary, AB, Canada dDepartment of Clinical and Experimental Medicine, Faculty of Medicine, University of Foggia, Foggia, Italy eDepartment of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands fDepartment of Animals in Science and Society, Division of Behavioural Neuroscience, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands Received 30 November 2014; received in revised form 25 February 2015; accepted 1 April 2015 KEYWORDS Abstract Endocannabinoid sys- To date, our understanding of the relative contribution and potential overlapping roles of the tem; endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in the regulation of Social behavior; brain function and behavior is still limited. To address this issue, we investigated the effects of Endocannabinoids; systemic administration of JZL195, that simultaneously increases AEA and 2-AG signaling by Emotional behavior; inhibiting their hydrolysis, in the regulation of socio-emotional behavior in adolescent and Rodents; adult rats. JZL195 JZL195, administered at the dose of 0.01 mg/kg, increased social play behavior, that is the most characteristic social activity displayed by adolescent rats, and increased social interaction in adult animals.
    [Show full text]
  • (THC) and Cannabidiol (CBD) in Male and Female Rats: Sex, Dose-Effec
    bioRxiv preprint doi: https://doi.org/10.1101/2021.05.11.443601; this version posted May 13, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Cannabinoid tetrad effects of oral Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in male and female rats: sex, dose-effects and time course evaluations Catherine F. Moore*, Elise M. Weerts Division of Behavioral Biology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD ∗ Corresponding author at: Johns Hopkins Bayview Research Campus, Behavioral Biology Research Center, 5510 Nathan Shock Drive, Suite 3000, Baltimore, MD 21224, USA. E-mail address: [email protected]. Tel: (410) 550-4316, Fax: (410) 550-0030. Acknowledgements All experiments were supported by the National Institute on Drug Abuse of the National Institutes of Health grant numbers R21DA046154 (EW) and the Johns Hopkins University Dalio Fund in Decision Making and the Neuroscience of Motivated Behaviors (EW). The authors have no conflicts of interest to disclose. 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.05.11.443601; this version posted May 13, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract Rationale The legalization of medicinal use of Cannabis sativa in most US states and the removal of hemp from the Drug Enforcement Agency (DEA) controlled substances act has resulted in a proliferation of products containing Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) for oral consumption (e.g., edibles, oils and tinctures) that are being used for recreational and medicinal purposes.
    [Show full text]
  • Inhibition of Milk Ingestion and Growth After Administration of a Neutral Cannabinoid CB1 Receptor Antagonist on the First Postnatal Day in the Mouse
    0031-3998/07/6205-0533 PEDIATRIC RESEARCH Vol. 62, No. 5, 2007 Copyright © 2007 International Pediatric Research Foundation, Inc. Printed in U.S.A. Inhibition of Milk Ingestion and Growth After Administration of a Neutral Cannabinoid CB1 Receptor Antagonist on the First Postnatal Day in the Mouse ESTER FRIDE, HILIT BRAUN, HILA MATAN, SHACHAR STEINBERG, PATRICIA H. REGGIO, AND HERBERT H. SELTZMAN Departments of Behavioral Sciences and Molecular Biology [E.F.], Department of Behavioral Sciences [H.B., H.M., S.S.], Ariel University Center of Samaria, Ariel 44837, Israel; Chemistry and Biochemistry Department [P.H.R.], Center for Drug Design, University of North Carolina, Greensboro, North Carolina 27402; Center for Organic and Medicinal Chemistry [H.H.S.], Research Triangle Institute, Research Triangle Park, North Carolina 27709 ABSTRACT: We have shown previously that neonatal exposure to tially present in CB1 receptor knockout pups (1). We have the cannabinoid CB1 receptor antagonist/inverse agonist rimonabant also suggested and presented preliminary data that show that (SR141716) interfered with suckling and development. However, it the impaired milk ingestion by the rimonabant-treated pups is was not clear whether the developmental deficiencies were induced due to an oral-motor weakness (3,4). by neutral CB1 receptor blockade, thereby inhibiting endogenous cannabinoid “tone,” or by inverse agonist reduction of constitutive Human infants with growth failure and low rates of food CB1 receptors. CB1 receptor blockade supports our hypothesis that intake, without any organic cause, are classified as suffering low CB1 receptor concentrations and/or reduced endocannabinoid from nonorganic failure to thrive (NOFTT). No treatment or levels underlie infant nonorganic failure to thrive (NOFTT).
    [Show full text]