Evaluación de la presencia y actividad de receptores cannabinoides en pulpa dental y odontoblastos humanos

ilustraciones, graficas

Autores:: Navarro Saiz, Laura Marcela

Tipo de recurso:

Fecha de publicación:: 2022

Institución:: Universidad Nacional de Colombia

Repositorio:: Universidad Nacional de Colombia

Idioma:: spa

id	UNACIONAL2_4884eaed760c5f905615a2640aa613a5
oai_identifier_str	oai:repositorio.unal.edu.co:unal/81731
network_acronym_str	UNACIONAL2
network_name_str	Universidad Nacional de Colombia
repository_id_str
dc.title.spa.fl_str_mv	Evaluación de la presencia y actividad de receptores cannabinoides en pulpa dental y odontoblastos humanos
dc.title.translated.eng.fl_str_mv	Evaluation of the presence and activity of cannabinoid receptors in dental pulp and human odontoblasts
title	Evaluación de la presencia y actividad de receptores cannabinoides en pulpa dental y odontoblastos humanos
spellingShingle	Evaluación de la presencia y actividad de receptores cannabinoides en pulpa dental y odontoblastos humanos 610 - Medicina y salud::617 - Cirugía, medicina regional, odontología, oftalmología, otología, audiología Pulpa Dental Receptores de Cannabinoides Dental Pulp Receptors, Cannabinoid Odontoblastos Dolor dental Receptor cannabinoide 1 (CB1) Receptor cannabinoide 2 (CB2) Pulpa dental Odontoblasts Dental pain Cannabinoid receptor 1 (CB1) Cannabinoid receptor 2 (CB2) Dental pulp
title_short	Evaluación de la presencia y actividad de receptores cannabinoides en pulpa dental y odontoblastos humanos
title_full	Evaluación de la presencia y actividad de receptores cannabinoides en pulpa dental y odontoblastos humanos
title_fullStr	Evaluación de la presencia y actividad de receptores cannabinoides en pulpa dental y odontoblastos humanos
title_full_unstemmed	Evaluación de la presencia y actividad de receptores cannabinoides en pulpa dental y odontoblastos humanos
title_sort	Evaluación de la presencia y actividad de receptores cannabinoides en pulpa dental y odontoblastos humanos
dc.creator.fl_str_mv	Navarro Saiz, Laura Marcela
dc.contributor.advisor.none.fl_str_mv	Castellanos Parra, Jaime Eduardo Bernal Cepeda, Lilia Jadith
dc.contributor.author.none.fl_str_mv	Navarro Saiz, Laura Marcela
dc.contributor.researchgroup.spa.fl_str_mv	IBAPO
dc.subject.ddc.spa.fl_str_mv	610 - Medicina y salud::617 - Cirugía, medicina regional, odontología, oftalmología, otología, audiología
topic	610 - Medicina y salud::617 - Cirugía, medicina regional, odontología, oftalmología, otología, audiología Pulpa Dental Receptores de Cannabinoides Dental Pulp Receptors, Cannabinoid Odontoblastos Dolor dental Receptor cannabinoide 1 (CB1) Receptor cannabinoide 2 (CB2) Pulpa dental Odontoblasts Dental pain Cannabinoid receptor 1 (CB1) Cannabinoid receptor 2 (CB2) Dental pulp
dc.subject.other.spa.fl_str_mv	Pulpa Dental Receptores de Cannabinoides
dc.subject.other.eng.fl_str_mv	Dental Pulp Receptors, Cannabinoid
dc.subject.proposal.spa.fl_str_mv	Odontoblastos Dolor dental Receptor cannabinoide 1 (CB1) Receptor cannabinoide 2 (CB2) Pulpa dental
dc.subject.proposal.eng.fl_str_mv	Odontoblasts Dental pain Cannabinoid receptor 1 (CB1) Cannabinoid receptor 2 (CB2) Dental pulp
description	ilustraciones, graficas
publishDate	2022
dc.date.accessioned.none.fl_str_mv	2022-07-22T19:43:02Z
dc.date.available.none.fl_str_mv	2022-07-22T19:43:02Z
dc.date.issued.none.fl_str_mv	2022-07-05
dc.type.spa.fl_str_mv	Trabajo de grado - Maestría
dc.type.driver.spa.fl_str_mv	info:eu-repo/semantics/masterThesis
dc.type.version.spa.fl_str_mv	info:eu-repo/semantics/acceptedVersion
dc.type.content.spa.fl_str_mv	Text
dc.type.redcol.spa.fl_str_mv	http://purl.org/redcol/resource_type/TM
status_str	acceptedVersion
dc.identifier.uri.none.fl_str_mv	https://repositorio.unal.edu.co/handle/unal/81731
dc.identifier.instname.spa.fl_str_mv	Universidad Nacional de Colombia
dc.identifier.reponame.spa.fl_str_mv	Repositorio Institucional Universidad Nacional de Colombia
dc.identifier.repourl.spa.fl_str_mv	https://repositorio.unal.edu.co/
url	https://repositorio.unal.edu.co/handle/unal/81731 https://repositorio.unal.edu.co/
identifier_str_mv	Universidad Nacional de Colombia Repositorio Institucional Universidad Nacional de Colombia
dc.language.iso.spa.fl_str_mv	spa
language	spa
dc.relation.references.spa.fl_str_mv	Sessle BJ. Peripheral and central mechanisms of orofacial inflammatory pain. . Translating Mechanisms Orofacial Neurological Disorder, 2011:179-206. Bae YC YA. Morphological fundamentals of pain processing in the dental pulp. J Oral Sci. 2020 2020;62(2):126-130. Maurin JC, Couble ML, Thivichon-Prince B, Magloire H. odontoblaste - Un acteur incontournable de la perception de la douleur dentinaire. Med Sci 2013;29(3):293-299. Lee K, Lee BM, Park CK, Kim YH, Chung G. Ion Channels Involved in Tooth Pain. Int J Mol Sci 2019;20(9):2266. Chung G, Jung SJ, Oh SB. Cellular and molecular mechanisms of dental nociception. J Dent Res 2013;92(11):948-55. . Solé-Magdalena A, Martínez-Alonso M, Coronado CA, Junquera LM, Cobo J, Vega JA. Molecular basis of dental sensitivity: The odontoblasts are multisensory cells and express multifunctional ion channels. . Ann Anat. 2018;215:20-29. Baldión PA, Velandia-Romero ML, Castellanos JE. Odontoblast-Like Cells Differentiated from Dental Pulp Stem Cells Retain Their Phenotype after Subcultivation. Int J Cell Biol 2018 Feb. Allard B, Magloire H, Couble ML, Maurin JC, Bleicher F. Voltage-gated sodium channels confer excitability to human odontoblasts: possible role in tooth pain transmission. J Biol Chem. 2013;281(39):29002-290010. Solé-Magdalena A, Revuelta EG, Menénez-Díaz I, Calavia MG, Cobo T, García-Suárez O, et al. Human odontoblasts express transient receptor protein and acid-sensing ion channel mechanosensor proteins. . Microsc Res Tech. 2011;74(5):457-63. Bleicher F. Odontoblast physiology. . Exp Cell Res. . 2014;325(2):65-71. Lee BM, Jo H, Park G, et al. Extracellular ATP Induces Calcium Signaling in Odontoblasts. J Dent Res. 2017;96(2):200-207. Starowicz K FD. Cannabinoids and Pain: Sites and Mechanisms of Action. Adv Pharmacol. 2017;80:437-475. Pertwee RG ea. International Union of Basic and Clinical Pharmacology. . . Pharmacol Rev. 2010;62:588-631. Wouters E, Walraed J, Banister SD, Stove CP. Insights into biased signaling at cannabinoid receptors: synthetic cannabinoid receptor agonists. Biochem Pharmacol 2019;169:113-623. Oddi S., Scipioni L, Maccarron M. Endocannabinoid system and adult neurogenesis: a focused review. . Opin Pharmacol. 2019;18(50):25-32. Zou S KU. Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System. Int J Mol Sci. 2018;19(3):833. Krishna. K, Kaavya et al. Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex. Cell 2019;176(3). Ye L, Cao Z, Wang W, Zhou N. New Insights in Cannabinoid Receptor Structure and Signaling. . Curr Mol Pharmacol. 2019;12(3):239-248 2019;12(3):239-248. Uniprot. UniProtKB-P21554 (CNR1_HUMAN). 2020; Available at: https://www.uniprot.org/uniprot/P21554. Genecards. Genomic location, CNR1 and CNR2 gene. 2021; Available at: https://www.genecards.org/cgi-bin/carddisp.pl?gene=CNR2&keywords=CNR2#genomic_location. B.S Basavarajappa. Cannabinoid Receptors and Their Signaling Mechanisms. The Endocannabinoid System 2017:25-62. CS Breivogel, G Griffin, V Di Marzo, BR Martin. Evidence for a new G protein-coupled cannabinoid receptor in mouse brain. Molecular pharmacology 2001;60(1):155-163. Kehua ea. Expression of Cannabinoid Type 1 Receptors in Human Odontoblast Cells. Journal Of Endodontic 2017;43(2):283-288. Howlett AC AM. CB1 and CB2 Receptor Pharmacology. Adv Pharmacol. 2017;80:169-206. Howlett AC AM. CB1 and CB2 Receptor Pharmacology. Adv Pharmacol. 2017;80:169-206. Miller LK, Devi LA. The highs and lows of cannabinoid receptor expression in disease: mechanisms and their therapeutic implications. Pharmacological reviews 2011 Sep;63(3):461-470. COSTIGAN M, SCHOLZ J, WOOLF CJ. Neuropathic Pain: A Maladaptive Response of the Nervous System to Damage. Annual review of neuroscience 2009;32(1):1-33. Börner C, Höllt V, Sebald W, Kraus J. Transcriptional regulation of the cannabinoid receptor type 1 gene in T cells by cannabinoids. Journal of leukocyte biology 2007 Jan 1,;81(1):336-343. Boerner C, Bedini A, Hoellt V, Kraus J. Analysis of Promoter Regions Regulating Basal and Interleukin-4-Inducible Expression of the Human CB1 Receptor Gene in T Lymphocytes. Molecular pharmacology 2008 Mar 1,;73(3):1013-1019. McKallip RJ, Nagarkatti M, Nagarkatti PS. Delta-9-tetrahydrocannabinol enhances breast cancer growth and metastasis by suppression of the antitumor immune response. The Journal of immunology (1950) 2005 Mar 15,;174(6):3281-3289. Wang D, Wang H, Ning W, Backlund MG, Dey SK, DuBois RN. Loss of Cannabinoid Receptor 1 Accelerates Intestinal Tumor Growth. Cancer Research 2008 Aug 1,;68(15):6468-6476. Izzo AA, Fezza F, Capasso R, Bisogno T, Pinto L, Iuvone T, et al. Cannabinoid CB1‐receptor mediated regulation of gastrointestinal motility in mice in a model of intestinal inflammation. British journal of pharmacology 2001 Oct;134(3):563-570. Julien B, Grenard P, Teixeira-Clerc F, Van Nhieu JT, Li L, Karsak M, et al. Antifibrogenic role of the cannabinoid receptor CB2 in the liver. Gastroenterology (New York, N.Y. 1943) 2005;128(3):742-755. Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Bátkai S, et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. The Journal of clinical investigation 2005 May;115(5):1298-1305. Jeong W, Osei-Hyiaman D, Park O, Liu J, Bátkai S, Mukhopadhyay P, et al. Paracrine Activation of Hepatic CB1 Receptors by Stellate Cell-Derived Endocannabinoids Mediates Alcoholic Fatty Liver. Cell Metabolism 2008 Mar;7(3):227-235. Kunos G, Osei-Hyiaman D, Liu J, Godlewski G, Bátkai S. Endocannabinoids and the Control of Energy Homeostasis. The Journal of biological chemistry 2008 Nov 28,;283(48):33021-33025. Vickers SP, Webster LJ, Wyatt A, Dourish CT, Kennett GA. Preferential effects of the cannabinoid CB1 receptor antagonist, SR 141716, on food intake and body weight gain of obese (fa/fa) compared to lean Zucker rats. Psychopharmacology 2003 Apr;167(1):103-111. Kim KW, Jo Y, Zhao L, Stallings NR, Chua SC, Parker KL. Steroidogenic Factor 1 Regulates Expression of the Cannabinoid Receptor 1 in the Ventromedial Hypothalamic Nucleus. Molecular endocrinology (Baltimore, Md.) 2008 Aug;22(8):1950-1961. Mach F, Steffens S, Veillard NR, Arnaud C, Pelli G, Burger F, et al. Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature 2005 Apr 7,;434(7034):782-786. Mach F, Steffens S, Veillard NR, Arnaud C, Pelli G, Burger F, et al. Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature 2005 Apr 7,;434(7034):782-786. Hungund BL, Vinod KY, Kassir SA, Basavarajappa BS, Yalamanchili R, Cooper TB, et al. Upregulation of CB1 receptors and agonist-stimulated [35S]GTPgammaS binding in the prefrontal cortex of depressed suicide victims. Molecular psychiatry 2004 Feb;9(2):184-190. Chiu CQ, Puente N, Grandes P, Castillo PE. Dopaminergic Modulation of Endocannabinoid-Mediated Plasticity at GABAergic Synapses in the Prefrontal Cortex. The Journal of neuroscience 2010 May 26,;30(21):7236-7248. Hay EA, Cowie P, Mcewan A, Wilson D, Ross R, Barrett P, et al. Genetic, epigenetic and pharmacological influences modulating tissue specific regulation of the cannabinoid receptor-1 gene (CB1); implications for cannabinoid pharmacogenetics. 2019 Feb 8,. Luo Y, Zhang J, Chen L, Chen S, Chen H, Zhang G, et al. Histone methyltransferase G9a diminishes expression of cannabinoid CB 1 receptors in primary sensory neurons in neuropathic pain. The Journal of biological chemistry 2020 Mar 13,;295(11):3553. Dhopeshwarkar A MK. Functional Selectivity of CB2 Cannabinoid Receptor Ligands at a Canonical and Noncanonical Pathway. J Pharmacol Exp Ther 2016;358(2):342-51. Unal H. Luciferase reporter assay for unlocking ligand-mediated signaling of GPCRs. Methods in Cell Biology. doi:10.1016/bs.mcb.2018.08.001 2018;149:19-30. Nobles KN, Xiao K, Ahn S, Shukla AK, Lam CM, Rajagopal S, et al. Distinct phosphorylation sites on the β(2)-adrenergic receptor establish a barcode that encodes differential functions of β-arrestin. . Sci Signal 2011;4(185):51. Mackie K, Lai Y, Westenbroek R, Mitchell R. Cannabinoids activate an inwardly rectifying potassium conductance and inhibit Q-type calcium currents in AtT20 cells transfected with rat brain cannabinoid receptor. The Journal of neuroscience 1995 Oct 1,;15(10):6552-6561. Haspula D, Clark MA. Cannabinoid Receptors: An Update on Cell Signaling, Pathophysiological Roles and Therapeutic Opportunities in Neurological, Cardiovascular, and Inflammatory Diseases. International journal of molecular sciences 2020 Oct 17,;21(20):7693. Nogueras-Ortiz C, Yudowski GA. The Multiple Waves of Cannabinoid 1 Receptor Signaling. Molecular pharmacology 2016 Nov;90(5):620-626. Delgado-Peraza F, Ahn KH, Nogueras-Ortiz C, Mungrue IN, Mackie K, Kendall DA, Yudowski GA. Mechanisms of Biased β-Arrestin-Mediated Signaling Downstream from the Cannabinoid 1 Receptor. Erratum in: Mol Pharmacol 2016;90(1):62. Nguyen PT, Schmid CL, Raehal KM, Selley DE, Bohn LM, Sim-Selley LJ. β-Arrestin2 Regulates Cannabinoid CB1 Receptor Signaling and Adaptation in a Central Nervous System Region–Dependent Manner. Biological psychiatry (1969) 2012;71(8):714-724. Ahn KH, Mahmoud MM, Shim J, Kendall DA. Distinct Roles of β-Arrestin 1 and β-Arrestin 2 in ORG27569-induced Biased Signaling and Internalization of the Cannabinoid Receptor 1 (CB1). The Journal of biological chemistry 2013 Apr 5,;288(14):9790-9800. Graham ES, Ball N, Scotter EL, Narayan P, Dragunow M, Glass M. Induction of Krox-24 by Endogenous Cannabinoid Type 1 Receptors in Neuro2A Cells Is Mediated by the MEK-ERK MAPK Pathway and Is Suppressed by the Phosphatidylinositol 3-Kinase Pathway. The Journal of biological chemistry 2006 Sep 29,;281(39):29085-29095. Haspula D, Clark MA. MAPK activation patterns of AT1R and CB1R in SHR versus Wistar astrocytes: Evidence of CB1R hypofunction and crosstalk between AT1R and CB1R. Cellular signalling 2017 Dec;40:81-90. Blázquez C, Chiarlone A, Bellocchio L, Resel E, Pruunsild P, García-Rincón D, et al. The CB₁ cannabinoid receptor signals striatal neuroprotection via a PI3K/Akt/mTORC1/BDNF pathway. Cell Death and Differentiation 2015 Oct;22(10):1618-1629. Chanda D, Kim D, Li T, Kim Y, Koo S, Lee C, et al. Cannabinoid Receptor Type 1 (CB1R) Signaling Regulates Hepatic Gluconeogenesis via Induction of Endoplasmic Reticulum-bound Transcription Factor cAMP-responsive Element-binding Protein H (CREBH) in Primary Hepatocytes. The Journal of biological chemistry 2011 Aug 12,;286(32):27971-27979. Bouaboula M, Poinot-Chazel C, Marchand J, Canat X, Bourrié B, Rinaldi-Carmona M, et al. Signaling Pathway Associated with Stimulation of CB2 Peripheral Cannabinoid Receptor. Involvement of Both Mitogen-Activated Protein Kinase and Induction of Krox-24 Expression. European journal of biochemistry 1996 May 1,;237(3):704-711. Nogueras-Ortiz C, Roman-Vendrell C, Mateo-Semidey GE, Liao Y, Kendall DA, Yudowski GA. Retromer stops beta-arrestin 1-mediated signaling from internalized cannabinoid 2 receptors. Molecular Biology of the Cell 2017 Nov 15,;28(24):3554-3561. Lauckner JE, Hille B, Mackie K. The cannabinoid agonist WIN55,212-2 increases intracellular calcium via CB1 receptor coupling to Gq/11 G proteins. Proceedings of the National Academy of Sciences - PNAS 2005 Dec 27,;102(52):19144-19149. Laprairie RB, Bagher AM, Kelly MEM, Dupré DJ, Denovan-Wright EM. Type 1 Cannabinoid Receptor Ligands Display Functional Selectivity in a Cell Culture Model of Striatal Medium Spiny Projection Neurons. The Journal of biological chemistry 2014 Sep 5,;289(36):24845-24862. Navarrete M, Araque A. Endocannabinoids Mediate Neuron-Astrocyte Communication. Neuron (Cambridge, Mass.) 2008;57(6):883-893. Zoratti C, Kipmen‐Korgun D, Osibow K, Malli R, Graier WF. Anandamide initiates Ca2+ signaling via CB2 receptor linked to phospholipase C in calf pulmonary endothelial cells. British journal of pharmacology 2003 Dec;140(8):1351-1362. Kearn CS, Blake-Palmer K, Daniel E, Mackie K, Glass M. Concurrent Stimulation of Cannabinoid CB1 and Dopamine D2 Receptors Enhances Heterodimer Formation: A Mechanism for Receptor Cross-Talk? Molecular pharmacology 2005 May 1,;67(5):1697-1704 CARRIBA P, ORTIZ O, CASADO V, CANELA EI, LLUIS C, GOLDBERG SR, et al. Striatal Adenosine A2A and Cannabinoid CB1 Receptors Form Functional Heteromeric Complexes that Mediate the Motor Effects of Cannabinoids. Neuropsychopharmacology (New York, N.Y.) 2007;32(11):2249-2259. Cinar R, Freund Tf, Katona I, Mackie K, Szucs M. Reciprocal inhibition of G-protein signaling is induced by CB1 cannabinoid and GABAB receptor interactions in rat hippocampal membranes. Neurochemistry international 2008;52(8):1402-1409. Rozenfeld R, Gupta A, Gagnidze K, Lim MP, Gomes I, Lee-Ramos D, et al. AT1R-CB1R heteromerization reveals a new mechanism for the pathogenic properties of angiotensin II. The EMBO journal 2011 Jun 15,;30(12):2350-2363. Callén L, Moreno E, Barroso-Chinea P, Moreno-Delgado D, Cortés A, Mallol J, et al. Cannabinoid Receptors CB1 and CB2 Form Functional Heteromers in Brain. The Journal of biological chemistry 2012 Jun 15,;287(25):20851-20865. Turu G, Várnai P, Gyombolai P, Szidonya L, Offertaler L, Bagdy G, et al. Paracrine Transactivation of the CB1 Cannabinoid Receptor by AT1 Angiotensin and Other Gq/11 Protein-coupled Receptors. The Journal of biological chemistry 2009 Jun 19,;284(25):16914-16921. Gyombolai P, Pap D, Turu G, Catt KJ, Bagdy G, Hunyady L. Regulation of endocannabinoid release by G proteins: A paracrine mechanism of G protein-coupled receptor action. Molecular and cellular endocrinology 2012 Apr 28,;353(1-2):29-36. Leterrier C, Bonnard D, Carrel D, Rossier J, Lenkei Z. Constitutive Endocytic Cycle of the CB1 Cannabinoid Receptor. The Journal of biological chemistry 2004 Aug 20,;279(34):36013-36021. Bénard G., Massa F., Puente N., Lourenço J., Bellocchio L., Soria-Gómez E., Matias I., Delamarre A., Metna-Laurent M., Cannich A., et al. Mitochondrial CB1 receptors regulate neuronal energy metabolism-Supplementary information. Nat. Neurosci 2012;15(558–564.). Miller LK, Devi LA. The highs and lows of cannabinoid receptor expression in disease: mechanisms and their therapeutic implications. Pharmacological reviews 2011 Sep;63(3):461-470. Laprairie R, Kelly M, Denovan‐Wright E. The dynamic nature of type 1 cannabinoid receptor (CB1) gene transcription. British journal of pharmacology 2012 Dec;167(8):1583-1595. Mukhopadhyay B, Liu J, Osei-Hyiaman D, Godlewski G, Mukhopadhyay P, Wang L, et al. Transcriptional Regulation of Cannabinoid Receptor-1 Expression in the Liver by Retinoic Acid Acting via Retinoic Acid Receptor-γ. The Journal of biological chemistry 2010 Jun 18,;285(25):19002-19011. Hegyi Z, Oláh T, Kőszeghy Á, Piscitelli F, Holló K, Pál B, et al. CB1 receptor activation induces intracellular Ca2+ mobilization and 2-arachidonoylglycerol release in rodent spinal cord astrocytes. Scientific Reports 2018 Jul 12,;8(1):1-16. Pertwee. Inverse agonism and neutral antagonism at cannabinoid CB1 receptors. Life Sci 2005;76:1307. Patel. et al. Cannabinoid CB1 receptor agonists produce cerebellar dysfunction in mice. J.Pharmacol.Exp.Ther :297-629. Micale et al. The cannabinoid CB1 antagonist TM38837 with limited penetrance to the brain shows reduced fear-promoting effects in mice. Front.Pharmacol 2019;10. German et al. Diarylureas as allosteric modulators of the cannabinoid CB1 receptor: structure-activity relationship studies on 1-(4-chlorophenyl)-3-{3-[6-(pyrrolidin-1-yl)pyridin-2-yl]phenyl}urea (PSNCBAM-1). . J.Med.Chem. 2014;57. Laprairie RB, Bagher AM, Kelly ME, Denovan-Wright EM. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol. 2015;172(20):4790-4805. Manera et al. Design, synthesis, and biological evaluation of new 1,8-naphthyridin-4(1H)-on-3-carboxamide and quinolin-4(1H)-on-3-carboxamide derivatives as CB2 selective agonists. J.Med.Chem ;49:5947. Pasquini et al. Investigations on the 4-quinolone-3-carboxylic acid motif. 2. Synthesis and structure-activity relationship of potent and selective cannabinoid-2 receptor agonists endowed with analgesic activity in vivo. J.Med.Chem ;51:5075. Gado et al. Identification of the first synthetic allosteric modulator of the CB2 receptors and evidence of its efficacy for neuropathic pain relief. J.Med.Chem 2019;62:276. Smith JS, Lefkowitz RJ, Rajagopal S. Biased signalling: from simple switches to allosteric microprocessors. Nat Rev Drug Discov. 2018 Apr;17(4):243-260. . 2018;17(4):243-260. Samama P, Cotecchia S, Costa T, Lefkowitz RJ. A mutation-induced activated state of the beta 2-adrenergic receptor. Extending the ternary complex model. The Journal of biological chemistry 1993 Mar 5,;268(7):4625-4636. Changeux J, Edelstein SJ. Allosteric Mechanisms of Signal Transduction. Science 2005 Jun 3,;308(5727):1424-1428. Kjelsberg MA, Cotecchia S, Ostrowski J, Caron MG, Lefkowitz RJ. Constitutive activation of the alpha 1B-adrenergic receptor by all amino acid substitutions at a single site. Evidence for a region which constrains receptor activation. The Journal of biological chemistry 1992 Jan 25,;267(3):1430-1433. Chen X, Bai B, Tian Y, Du H, Chen J. Identification of Serine 348 on the Apelin Receptor as a Novel Regulatory Phosphorylation Site in Apelin-13-induced G Protein-independent Biased Signaling. The Journal of biological chemistry 2014 Nov 7,;289(45):31173-31187. Wanka L, Babilon S, Burkert K, Mörl K, Gurevich VV, Beck-Sickinger AG. C-terminal motif of human neuropeptide Y4 receptor determines internalization and arrestin recruitment. Cellular signalling 2017 Jan;29:233-239. Zidar DA, Violin JD, Whalen EJ, Lefkowitz RJ. Selective Engagement of G Protein Coupled Receptor Kinases (GRKs) Encodes Distinct Functions of Biased Ligands. Proceedings of the National Academy of Sciences - PNAS 2009 Jun 16,;106(24):9649-9654. Urs NM, Gee SM, Pack TF, McCorvy JD, Evron T, Snyder JC, et al. Distinct cortical and striatal actions of a β-arrestin–biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties. Proceedings of the National Academy of Sciences - PNAS 2016 Dec 13,;113(50):E8178-E8186. Navarro G, Reyes-Resina I, Rivas-Santisteban R, Sánchez de Medina V, Morales P. Cannabidiol skews biased agonism at cannabinoid CB1 and CB2 receptors with smaller effect in CB1-CB2 heteroreceptor complexes. Biochem Pharmacol 2018;157:148-158. Maayah ZH, Takahara S, Ferdaoussi M, Dyck JRB. The molecular mechanisms that underpin the biological benefits of full-spectrum cannabis extract in the treatment of neuropathic pain and inflammation. Biochim Biophys Acta Mol Basis Dis 2020;1866(7):165771. P. Pacher, S. Batkai, G. Kunos. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol. Rev. 2006;58:389–462. A. Bilkei-Gorzo, O. Albayram, A. Draffehn, K. Michel, A. Piyanova, H. Oppenheimer. A chronic low dose of Delta(9)-tetrahydrocannabinol (THC) restores cognitive function in old mice. Nat. Med 2017;23:782–787. C. Ibeas Bih, T. Chen, A.V. Nunn, M. Bazelot, M. Dallas, B.J. Whalley. Molecular targets of Cannabidiol in neurological disorders, Neurotherapeutics. The Journal of the American Society for Experimental NeuroTherapeutics 2015;12:699–730. P. Seeman. Cannabidiol is a partial agonist at dopamine D2High receptors, predicting its antipsychotic clinical dose. Transl. Psychiatry 2016;6:920. F.V. Gomes, L.B. Resstel, F.S. Guimaraes. The anxiolytic-like effects of cannabidiol injected into the bed nucleus of the stria terminalis are mediated by 5-HT1A receptors. Psychopharmacology 2011;213:465–473. L. De Petrocellis, A. Ligresti, A.S. Moriello, M. Allara, T. Bisogno, S. Petrosino, C.G. Stott, V. Di Marzo. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Pharmacol. 2011;163:1479–1494. Ruhaak LR, Felth J, Karlsson PC, Rafter JJ, Verpoorte R, Bohlin L, 34(5):774-8. Evaluation of the cyclooxygenase inhibiting effects of six major cannabinoids isolated from Cannabis sativa. Biol Pharm Bull. 2011;34(5):774-8. 2011;34(5):774-778. DeLong GT, Wolf CE, Poklis A, Lichtman AH. Pharmacological evaluation of the natural constituent of Cannabis sativa, cannabichromene and its modulation by Δ(9)-tetrahydrocannabinol. Drug and alcohol dependence 2010 Nov 1,;112(1-2):126-133. Cascio MG, Gauson LA, Stevenson LA, Ross RA, Pertwee RG. Evidence that the plant cannabinoid cannabigerol is a highly potent alpha2-adrenoceptor agonist and moderately potent 5HT1A receptor antagonist. British journal of pharmacology 2010 Jan;159(1):129-141. Comelli F, Giagnoni G, Bettoni I, Colleoni M, Costa B. Antihyperalgesic effect of a Cannabis sativa extract in a rat model of neuropathic pain: mechanisms involved. Phytotherapy research 2008 Aug;22(8):1017-1024. Miyazawa M, Yamafuji C. Inhibition of Acetylcholinesterase Activity by Bicyclic Monoterpenoids. Journal of agricultural and food chemistry 2005 Mar 9,;53(5):1765-1768. Klauke A-, Racz I, Pradier B, Markert A, Zimmer AM, Gertsch J, et al. The cannabinoid CB.sub.2 receptor-selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain. European neuropsychopharmacology 2014 Apr 1,;24(4):608. Alberti TB, Barbosa WLR, Vieira JLF, Raposo NRB, Dutra RC. (−)-β-Caryophyllene, a CB2 Receptor-Selective Phytocannabinoid, Suppresses Motor Paralysis and Neuroinflammation in a Murine Model of Multiple Sclerosis. International journal of molecular sciences 2017 Apr 1,;18(4):691. Kim HJ, Kim B, Park BM, Jeon JE, Lee SH, Mann S, et al. Topical cannabinoid receptor 1 agonist attenuates the cutaneous inflammatory responses in oxazolone-induced atopic dermatitis model. International journal of dermatology 2015 Oct;54(10):e401-e408. Maresz K, Carrier EJ, Ponomarev ED, Hillard CJ, Dittel BN. Modulation of the cannabinoid CB2 receptor in microglial cells in response to inflammatory stimuli. Journal of neurochemistry 2005 Oct;95(2):437-445. (109) Galán-Ganga M, del Río R, Jiménez-Moreno N, Díaz-Guerra M, Lastres-Becker I. Cannabinoid CB2 Receptor Modulation by the Transcription Factor NRF2 is Specific in Microglial Cells. Cellular and molecular neurobiology 2020 Jan 1,;40(1):167-177. Gaffal E, Cron M, Glodde N, Tüting T. Anti‐inflammatory activity of topical THC in DNFB‐mediated mouse allergic contact dermatitis independent of CB1 and CB2 receptors. Allergy (Copenhagen) 2013 Aug;68(8):994-1000. Philpott HT, OʼBrien M, McDougall JJ. Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis. Pain (Amsterdam) 2017 Dec;158(12):2442-2451. Schuelert N, McDougall JJ. Cannabinoid‐mediated antinociception is enhanced in rat osteoarthritic knees. Arthritis and rheumatism 2008 Jan;58(1):145-153. Romero V, Lara JR, Otero-Espinar F, Salgado MH, Modolo NSP, Barros, Guilherme Antonio Moreira de. Capsaicin topical cream (8%) for the treatment of myofascial pain syndrome. Revista brasileira de anestesiologia 2019 Sep;69(5):432-438. Xu DH, Cullen BD, Tang M, Fang Y. The Effectiveness of Topical Cannabidiol Oil in Symptomatic Relief of Peripheral Neuropathy of the Lower Extremities. Current pharmaceutical biotechnology 2020;21(5):390-402. Nitecka-Buchta A, Nowak-Wachol A, Wachol K, Walczyńska-Dragon K, Olczyk P, Batoryna O, et al. Myorelaxant Effect of Transdermal Cannabidiol Application in Patients with TMD: A Randomized, Double-Blind Trial. Journal of clinical medicine 2019 Nov 6,;8(11):1886. García-Andreu J. Manejo básico del dolor agudo y crónico. Anest Méx 2017;29:77-85. Julius D, Allan I. Molecular mechanisms of nociception. Nature 2001;413:203-210. Solé-Magdalena A, Revuelta EG, Menénez-Díaz I, Calavia MG, et al. Human odontoblasts express transient receptor protein and acid-sensing ion channel mechanosensor proteins. Microsc Res Tech 2011;74(5):457-63. Smith PC, Martínez C, Martínez J, McCulloch CA. Role of Fibroblast Populations in Periodontal Wound Healing and Tissue Remodeling. Front Physiol 2019;10:270. Haspula D, Clark MA. Cannabinoid Receptors: An Update on Cell Signaling, Pathophysiological Roles and Therapeutic Opportunities in Neurological, Cardiovascular, and Inflammatory Diseases. Int J Mol Sci 2020;21(20):7693. Philpott HT, OʼBrien M, McDougall JJ. Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis. Pain 2017;158(12):2442-2451. Konermann A, Jäger A, Held SAE, Brossart P, et al. In vivo and In vitro Identification of Endocannabinoid Signaling in Periodontal Tissues and Their Potential Role in Local Pathophysiology. Cell Mol Neurobiol 2017;37(8):1511-1520. Qian H, Zhao Y, Peng Y, Han C, et al. Activation of cannabinoid receptor CB2 regulates osteogenic and osteoclastogenic gene expression in human periodontal ligament cells. J Periodontal Res 2010; 45(4):504-11. Ossola CA, Surkin PN, Mohn CE, Elverdin JC, et al. Anti-Inflammatory and Osteoprotective Effects of Cannabinoid-2 Receptor Agonist HU-308 in a Rat Model of Lipopolysaccharide-Induced Periodontitis. J Periodontol 2016;87(6):725-34. Picciolo G, Pallio G, Altavilla D, Vaccaro M, et al. β-Caryophyllene Reduces the Inflammatory Phenotype of Periodontal Cells by Targeting CB2 Receptors. Biomedicines 2020;8(6):164 Schefe JH, Lehmann KE, Buschmann IR, Unger T, et al. Quantitative real-time RT-PCR data analysis: current concepts and the novel gene expression's CT difference formula. J Mol Med 2006;84(11):901-910. Beneng K, Renton T, Yilmaz Z, Yiangou Y, et al. Cannabinoid receptor CB1-immunoreactive nerve fibres in painful and non-painful human tooth pulp. J Clin Neurosci 2010;17(11):1476–1479. Somsak M, Sopee P, Pornpoj F. Cannabinoid receptor 1 (CB1R) expression in rat dental pulp. Oral Sci Int 2012;9(1):17-20. Prada-Arismendy J, Castellanos JE. Real time PCR. Application in dengue studies. Colombia médica (Cali, Colombia) 2011 Jun 6,;42(2):243-258. Köhsler M, Leitsch D, Müller N, Walochnik J. Validation of reference genes for the normalization of RT-qPCR gene expression in Acanthamoeba spp. Scientific reports 2020 Jun 25,;10(1):10362. Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M, et al. The MIQE Guidelines: Minimum Information for Publication of Quantitative Real-Time PCR Experiments. Clinical chemistry (Baltimore, Md.) 2009 Apr 1,;55(4):611-622. Romero Geraldo R, Hernández Saavedra N, Fimbres Olivarría D, García Lagunas N. Validation of suitable reference genes for quantitative real-time PCR normalization in Crassostrea gigas spat stage during toxic dinoflagellates exposure. Biotecnia 2020;22(2):94-102. Dheda K, Huggett JF, Bustin SA, Johnson MA, Rook G, ZumLa A. Validation of housekeeping genes for normalizing RNA expression in real-time PCR. BioTechniques 2004 Jul 1,;37(1):112-119. Suzuki T, Higgins PJ, Crawford DR. Control Selection for RNA Quantitation. BioTechniques 2000 Aug 1,;29(2):332-337. Chapman JR, Waldenström J. With Reference to Reference Genes: A systematic review of endogenous controls in gene expression studies. PloS one 2015;10(11):e0141853. Hruz T, Wyss M, Docquier M, Pfaffl MW, Masanetz S, Borghi L, et al. RefGenes: identification of reliable and condition specific reference genes for RT-qPCR data normalization. BMC genomics 2011 Mar 21,;12(1):156. Ito S, Gojoubori T, Tsunoda K, Yamaguchi Y, Asano M, Goke E, et al. Nicotine-induced expression of low-density lipoprotein receptor in oral epithelial cells. PLoS ONE 2013;8(12):e82563. Ockenga W, Kühne S, Bocksberger S, Banning A, Tikkanen R. Epidermal growth factor receptor transactivation is required for mitogen-activated protein kinase activation by muscarinic acetylcholine receptors in HaCaT keratinocytes. International Journal of Molecular Sciences 2014 Nov 21,;15(11):21433-21454. Graeser A, Huebbe P, Storm N, Höppner W, Döring F, Wagner AE, et al. Apolipoprotein E genotype affects tissue metallothionein levels: studies in targeted gene replacement mice. Genes & nutrition 2012 Apr;7(2):247-255. Zheng X, Rao X, Gomez-Gutierrez JG, Hao H, McMasters KM, Zhou HS. Adenovirus E1B55K Region Is Required To Enhance Cyclin E Expression for Efficient Viral DNA Replication. Journal of Virology 2008 Apr 1,;82(7):3415-3427. Vuong HG, Kondo T, Oishi N, Nakazawa T, Mochizuki K, Miyauchi A, et al. Paediatric follicular thyroid carcinoma – indolent cancer with low prevalence of RAS mutations and absence of PAX8–PPARG fusion in a Japanese population. Histopathology 2017 Nov;71(5):760-768. Nikiforova MN, Biddinger PW, Caudill CM, Kroll TG, Nikiforov YE. PAX8-PPARgamma rearrangement in thyroid tumors: RT-PCR and immunohistochemical analyses. The American journal of surgical pathology 2002 Aug;26(8):1016-1023. Lim H, Nam OH, Kim M, El-Fiqi A, Yun H, Lee Y, et al. Delivery of dexamethasone from bioactive nanofiber matrices stimulates odontogenesis of human dental pulp cells through integrin/BMP/mTOR signaling pathways. International Journal of Nanomedicine 2016;11:2557-2567. Mar JC, Kimura Y, Schroder K, Irvine KM, Hayashizaki Y, Suzuki H, et al. Data-driven normalization strategies for high-throughput quantitative RT-PCR. BMC Bioinformatics 2009 Apr 19,;10(1):110. Pfaffl M, Tichopad A, Prgomet C, Neuvians T. Determination of stable housekeeping genes, differentially regulated target genes and sample integrity: BestKeeper – Excel-based tool using pair-wise correlations. Biotechnology Letters 2004 Mar;26(6):509-515. Maresz K, Carrier EJ, Ponomarev ED, Hillard CJ, Dittel BN. Modulation of the cannabinoid CB2 receptor in microglial cells in response to inflammatory stimuli. Journal of neurochemistry 2005 Oct;95(2):437-445. Nakajima Y, Furuichi Y, Biswas KK, Hashiguchi T, et al. Endocannabinoid, anandamide in gingival tissue regulates the periodontal inflammation through NF-kappaB pathway inhibition. FEBS Lett 2006;580(2):613-9. Ibeas C, Chen T, Nunn VM, Bazelot, et al. Molecular targets of Cannabidiol in neurological disorders, Neurotherapeutics. NeuroTherapeutics 2015;12:699–730. Seeman P. Cannabidiol is a partial agonist at dopamine D2High receptors, predicting its antipsychotic clinical dose. Transl Psychiatry 2016;6:920. Gomes FV, Resstel LB, Guimaraes FS. The anxiolytic-like effects of cannabidiol injected into the bed nucleus of the stria terminalis are mediated by 5-HT1A receptors. Psychopharmacology 2011;213:465–473. De Petrocellis L, Ligresti A, Moriello AS, Allara M, et al. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Pharmacol 2011;163:1479–1494. Ruhaak LR, Felth J, Karlsson PC, Rafter JJ. Evaluation of the cyclooxygenase inhibiting effects of six major cannabinoids isolated from Cannabis sativa. Biol Pharm Bull 2011;34(5):774-8 de Almeida DL, Devi LA. Diversity of molecular targets and signaling pathways for CBD. Pharmacol Res Perspect 2020;8(6). Kassebaum NJ, Bernabé E, Dahiya M, Bhandari B, Murray CJL, Marcenes W. Global Burden of Untreated Caries. Journal of Dental Research 2015 May;94(5):650-658 Hossain MZ, Bakri MM, Yahya F, Ando H, Unno S, Kitagawa J. The role of transient receptor potential (TRP) channels in the transduction of dental pain. International Journal of Molecular Sciences 2019 Jan 27,;20(3):526. Pergolizzi JV, Magnusson P, LeQuang JA, Gharibo C, Varrassi G. The pharmacological management of dental pain. Expert opinion on pharmacotherapy 2020 Mar 23,;21(5):591-601. Julius D AI. Molecular mechanisms of nociception. Nature 2001;413:203-210. Ardila.C.M. Hipersensibilidad dentinal: Una revisión de su etiología, patogénesis y tratamiento. Av Odontoestomatol . 2009;25:137-146. Shibukawa Y, Sato M, Kimura M, Sobhan U, Shimada M, Nishiyama A, et al. Odontoblasts as sensory receptors: transient receptor potential channels, pannexin-1, and ionotropic ATP receptors mediate intercellular odontoblast-neuron signal transduction. Pflugers Arch. 2015;467(4):843-463 Munt ea. THC and Cannabinol Activate Sensory Nerves. J. Neurosci 2002;22(11):4720–4727 M. L. Velandia, J. V. Montoya, M. Martínez, S. Perdomo, and J. E. Castellanos. Comparison of three neuro-tracing techniques for identification of the sciatic spinal nerve origin in mice. Biomédica 2002;22(4):529–534 Thermo Fisher. Electrofisiology protocol. Available at: https://www.thermofisher.com/co/en/home/references/protocols/neurobiology/neurobiology-protocols/electrophysiology.htmL. Farges J, Carrouel F, Keller J, Baudouin C, Msika P, Bleicher F, et al. Cytokine production by human odontoblast-like cells upon Toll-like receptor-2 engagement. Immunobiology (1979) 2010;216(4):513-517. Pääkkönen V, Rusanen P, Hagström J, Tjäderhane L. Mature human odontoblasts express virus-recognizing toll-like receptors. International endodontic journal 2014 Oct;47(10):934-941. Botero TM, Shelburne CE, Holland GR, Hanks CT, Nör JE. TLR4 Mediates LPS-Induced VEGF Expression in Odontoblasts. Journal of endodontics 2006;32(10):951-955. Kawasaki Takumi, Kawai Taro. Toll-like receptor signaling pathways. Front. Immunol 2014 25 September. Caviedes-Bucheli, Javier, DDS, MSc, Muñoz, Hugo Roberto, DDS, MSc, Azuero-Holguín MM, DDS, Ulate E, DDS. Neuropeptides in Dental Pulp: The Silent Protagonists. Journal of endodontics 2008;34(7):773-788 McCoy KL. Interaction between Cannabinoid System and Toll-Like Receptors Controls Inflammation. Mediators of Inflammation 2016 Aug 11,;2016:5831315-18. Allard B, Magloire H, Couble ML, Maurin JC, Bleicher F. Voltage-gated sodium channels confer excitability to human odontoblasts: possible role in tooth pain transmission. J Biol Chem. 2013;281(39):29002-290010. Caviedes-Bucheli J, Gutierrez-Guerra JE, Salazar F, Pichardo D, Moreno GC, Munoz HR. Substance P receptor expression in healthy and inflamed human pulp tissue. International endodontic journal 2007 Feb;40(2):106-111. Darmani NA, Belkacemi L, Zhong W. Δ9-THC and related cannabinoids suppress substance P- induced neurokinin NK1-receptor-mediated vomiting via activation of cannabinoid CB1 receptor. European journal of pharmacology 2019 Dec 15,;865:172806 Oshita K, Inoue A, Tang H, Nakata Y, Kawamoto M, Yuge O. CB1 Cannabinoid Receptor Stimulation Modulates Transient Receptor Potential Vanilloid Receptor 1 Activities in Calcium Influx and Substance P Release in Cultured Rat Dorsal Root Ganglion Cells. Journal of Pharmacological Sciences 2005;97(3):377-385. Kibret BG, Ishiguro H, Horiuchi Y, Onaivi ES. New Insights and Potential Therapeutic Targeting of CB2 Cannabinoid Receptors in CNS Disorders. International journal of molecular sciences 2022 Jan 17,;23(2):975. Shohami E, Cohen‐Yeshurun A, Magid L, Algali M, Mechoulam R. Endocannabinoids and traumatic brain injury. British journal of pharmacology 2011 Aug;163(7):1402-1410 Patil M, Patwardhan A, Salas MM, Hargreaves KM, Akopian AN. Cannabinoid receptor antagonists AM251 and AM630 activate TRPA1 in sensory neurons. Neuropharmacology 2011;61(4):778-788 Bakali E, Tincello D. Current Understanding of Cannabinoids and Detrusor Overactivity. Curr Bladder Dysfunct Rep 2017 Mar 7,;12(1):86-94.
dc.rights.coar.fl_str_mv	http://purl.org/coar/access_right/c_abf2
dc.rights.license.spa.fl_str_mv	Reconocimiento 4.0 Internacional
dc.rights.uri.spa.fl_str_mv	http://creativecommons.org/licenses/by/4.0/
dc.rights.accessrights.spa.fl_str_mv	info:eu-repo/semantics/openAccess
rights_invalid_str_mv	Reconocimiento 4.0 Internacional http://creativecommons.org/licenses/by/4.0/ http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv	openAccess
dc.format.extent.spa.fl_str_mv	84 páginas
dc.format.mimetype.spa.fl_str_mv	application/pdf
dc.publisher.spa.fl_str_mv	Universidad Nacional de Colombia
dc.publisher.program.spa.fl_str_mv	Bogotá - Odontología - Maestría en Odontología
dc.publisher.faculty.spa.fl_str_mv	Facultad de Odontología
dc.publisher.place.spa.fl_str_mv	Bogotá, Colombia
dc.publisher.branch.spa.fl_str_mv	Universidad Nacional de Colombia - Sede Bogotá
institution	Universidad Nacional de Colombia
bitstream.url.fl_str_mv	https://repositorio.unal.edu.co/bitstream/unal/81731/1/Documento%20tesis%20Laura%20M%20Navarro-Saiz.pdf https://repositorio.unal.edu.co/bitstream/unal/81731/2/license.txt https://repositorio.unal.edu.co/bitstream/unal/81731/3/Documento%20tesis%20Laura%20M%20Navarro-Saiz.pdf.jpg
bitstream.checksum.fl_str_mv	9da7f5c95614db989462f2ebd9dc6a4d 8153f7789df02f0a4c9e079953658ab2 1c056af1cae4b2d718de586b3d3dca7b
bitstream.checksumAlgorithm.fl_str_mv	MD5 MD5 MD5
repository.name.fl_str_mv	Repositorio Institucional Universidad Nacional de Colombia
repository.mail.fl_str_mv	repositorio_nal@unal.edu.co
_version_	1814089958740197376
spelling	Reconocimiento 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Castellanos Parra, Jaime Eduardod005422b5147ff1af3f046ffaf4328e6Bernal Cepeda, Lilia Jadith77fe9bc1954046f69b1bd6a7658a0f27Navarro Saiz, Laura Marcelaf97fae205729550e65e2a32eb4d54b4bIBAPO2022-07-22T19:43:02Z2022-07-22T19:43:02Z2022-07-05https://repositorio.unal.edu.co/handle/unal/81731Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/ilustraciones, graficasLa inflamación, la sensibilidad y el dolor dental continúan siendo un reto en la práctica odontológica, es por esa razón que la búsqueda de alternativas farmacológicas para su control es una necesidad. En ese sentido los receptores cannabinoides CB1 y CB2 resultan una alternativa para ser utilizados como nuevos blancos terapéuticos. Dado que no se encontró evidencia en la literatura de su presencia en la pulpa dental y en odontoblastos en condiciones de inflamación, este trabajo de tesis tuvo como objetivo evaluar su expresión y funcionalidad en esas condiciones. Este trabajo está dividido en 4 capítulos: en el Capítulo 1 se realizó una revisión bibliográfica en la que se exploró la fisiología de los cannabinoides y de ambos receptores. Dado que no se encontró evidencia de la validación de genes de referencia en odontoblastos humanos en contexto inflamatorio, en el Capítulo 2 se describió una estrategia metodológica para la elección de los genes de referencia más adecuados para la realización de la cuantificación relativa de los receptores cannabinoides por medio de RT-qPCR. En el siguiente Capítulo, se comparó la presencia y actividad de receptores cannabinoides en odontoblastos humanos y en fibroblastos gingivales ya que ambas células tienen un papel importante en la modulación de la inflamación y el dolor en pulpitis y periodontitis. Finalmente, en el Capítulo 4 se evalúa la presencia de CB1 y CB2 en pulpas dentales y la presencia y actividad en cultivo de odontoblastos humanos en condiciones de inflamación. Esto permitió aportar luces sobre el papel de los receptores cannabinoides en el dolor e inflamación en odontología, y además de comprobar su expresión y modulación en células y tejidos dentales, abriendo paso a nuevas investigaciones que usen agonistas de ambos receptores para el control del dolor y la inflamación en encía y pulpa dental. (Texto tomado de la fuente)Inflammation, sensitivity and dental pain continue to be a challenge in dental practice, which is why the search for pharmacological alternatives for their control is a necessity. In this sense, CB1 and CB2 cannabinoid receptors are an alternative to be used as new therapeutic targets. Since no evidence was found in the literature of their presence in dental pulp and odontoblasts under inflammatory conditions, the aim of this thesis was to evaluate their expression and functionality under these conditions. This work is divided into 4 chapters: in Chapter 1, a literature review was conducted in which the physiology of cannabinoids and both receptors was explored. Since no evidence was found for the validation of reference genes in human odontoblasts in an inflammatory context, Chapter 2 described a methodological strategy for the choice of the most suitable reference genes for the relative quantification of cannabinoid receptors by RT-qPCR. In the next chapter, the presence and activity of cannabinoid receptors in human odontoblasts and gingival fibroblasts were compared as both cells play an important role in the modulation of inflammation and pain in pulpitis and periodontitis. Finally, Chapter 4 evaluates the presence of CB1 and CB2 in dental pulps and the presence and activity in cultured human odontoblasts under inflammatory conditions. This allowed us to shed light on the role of cannabinoid receptors in pain and inflammation in dentistry, and also to verify their expression and modulation in dental cells and tissues, opening the way to new research using agonists of both receptors for the control of pain and inflammation in gingiva and dental pulp.MaestríaMagíster en OdontologíaEstudio experimental in vitro cuantitativo y semicuantitativo. Se utilizarán células similares a odontoblastos y cortes histológicos de dientes sanos y cariados, se evaluará la expresión de receptores cannabinoides CB1 y CB2 por medio de RT- qPCR. En los cortes histológicos se realizarán inmunoperoxidasas e inmunofluorescencias con el fin de determinar la presencia y localización de los receptores en pulpa dental sana e inflamada. La actividad in vitro, sobre OLC de CB1 y CB2 se determinará usando la sonda para calcio Fluo-4, haciendo tratamiento con diferentes agonistas y antagonistas para evaluar los influjos de calcio y de esta manera evaluar su funcionalidad. Finalmente se realizarán los análisis estadísticos de las réplicas de cada experimento para determinar las significancias estadísticas para el posterior análisis de resultados. Con los datos obtenidos se podrá evaluar si los OLC y la pulpa dental humana expresan estos receptores y si son funcionales, además se determinará si existen cambios en los patrones de expresión de los receptores en dientes cariados y no cariados.Fisiopatología del dolor pulpar84 páginasapplication/pdfspaUniversidad Nacional de ColombiaBogotá - Odontología - Maestría en OdontologíaFacultad de OdontologíaBogotá, ColombiaUniversidad Nacional de Colombia - Sede Bogotá610 - Medicina y salud::617 - Cirugía, medicina regional, odontología, oftalmología, otología, audiologíaPulpa DentalReceptores de CannabinoidesDental PulpReceptors, CannabinoidOdontoblastosDolor dentalReceptor cannabinoide 1 (CB1)Receptor cannabinoide 2 (CB2)Pulpa dentalOdontoblastsDental painCannabinoid receptor 1 (CB1)Cannabinoid receptor 2 (CB2)Dental pulpEvaluación de la presencia y actividad de receptores cannabinoides en pulpa dental y odontoblastos humanosEvaluation of the presence and activity of cannabinoid receptors in dental pulp and human odontoblastsTrabajo de grado - Maestríainfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/acceptedVersionTexthttp://purl.org/redcol/resource_type/TMSessle BJ. Peripheral and central mechanisms of orofacial inflammatory pain. . Translating Mechanisms Orofacial Neurological Disorder, 2011:179-206.Bae YC YA. Morphological fundamentals of pain processing in the dental pulp. J Oral Sci. 2020 2020;62(2):126-130.Maurin JC, Couble ML, Thivichon-Prince B, Magloire H. odontoblaste - Un acteur incontournable de la perception de la douleur dentinaire. Med Sci 2013;29(3):293-299.Lee K, Lee BM, Park CK, Kim YH, Chung G. Ion Channels Involved in Tooth Pain. Int J Mol Sci 2019;20(9):2266.Chung G, Jung SJ, Oh SB. Cellular and molecular mechanisms of dental nociception. J Dent Res 2013;92(11):948-55. .Solé-Magdalena A, Martínez-Alonso M, Coronado CA, Junquera LM, Cobo J, Vega JA. Molecular basis of dental sensitivity: The odontoblasts are multisensory cells and express multifunctional ion channels. . Ann Anat. 2018;215:20-29.Baldión PA, Velandia-Romero ML, Castellanos JE. Odontoblast-Like Cells Differentiated from Dental Pulp Stem Cells Retain Their Phenotype after Subcultivation. Int J Cell Biol 2018 Feb.Allard B, Magloire H, Couble ML, Maurin JC, Bleicher F. Voltage-gated sodium channels confer excitability to human odontoblasts: possible role in tooth pain transmission. J Biol Chem. 2013;281(39):29002-290010.Solé-Magdalena A, Revuelta EG, Menénez-Díaz I, Calavia MG, Cobo T, García-Suárez O, et al. Human odontoblasts express transient receptor protein and acid-sensing ion channel mechanosensor proteins. . Microsc Res Tech. 2011;74(5):457-63.Bleicher F. Odontoblast physiology. . Exp Cell Res. . 2014;325(2):65-71.Lee BM, Jo H, Park G, et al. Extracellular ATP Induces Calcium Signaling in Odontoblasts. J Dent Res. 2017;96(2):200-207.Starowicz K FD. Cannabinoids and Pain: Sites and Mechanisms of Action. Adv Pharmacol. 2017;80:437-475.Pertwee RG ea. International Union of Basic and Clinical Pharmacology. . . Pharmacol Rev. 2010;62:588-631.Wouters E, Walraed J, Banister SD, Stove CP. Insights into biased signaling at cannabinoid receptors: synthetic cannabinoid receptor agonists. Biochem Pharmacol 2019;169:113-623.Oddi S., Scipioni L, Maccarron M. Endocannabinoid system and adult neurogenesis: a focused review. . Opin Pharmacol. 2019;18(50):25-32.Zou S KU. Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System. Int J Mol Sci. 2018;19(3):833.Krishna. K, Kaavya et al. Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex. Cell 2019;176(3).Ye L, Cao Z, Wang W, Zhou N. New Insights in Cannabinoid Receptor Structure and Signaling. . Curr Mol Pharmacol. 2019;12(3):239-248 2019;12(3):239-248.Uniprot. UniProtKB-P21554 (CNR1_HUMAN). 2020; Available at: https://www.uniprot.org/uniprot/P21554.Genecards. Genomic location, CNR1 and CNR2 gene. 2021; Available at: https://www.genecards.org/cgi-bin/carddisp.pl?gene=CNR2&keywords=CNR2#genomic_location.B.S Basavarajappa. Cannabinoid Receptors and Their Signaling Mechanisms. The Endocannabinoid System 2017:25-62.CS Breivogel, G Griffin, V Di Marzo, BR Martin. Evidence for a new G protein-coupled cannabinoid receptor in mouse brain. Molecular pharmacology 2001;60(1):155-163.Kehua ea. Expression of Cannabinoid Type 1 Receptors in Human Odontoblast Cells. Journal Of Endodontic 2017;43(2):283-288.Howlett AC AM. CB1 and CB2 Receptor Pharmacology. Adv Pharmacol. 2017;80:169-206.Howlett AC AM. CB1 and CB2 Receptor Pharmacology. Adv Pharmacol. 2017;80:169-206.Miller LK, Devi LA. The highs and lows of cannabinoid receptor expression in disease: mechanisms and their therapeutic implications. Pharmacological reviews 2011 Sep;63(3):461-470.COSTIGAN M, SCHOLZ J, WOOLF CJ. Neuropathic Pain: A Maladaptive Response of the Nervous System to Damage. Annual review of neuroscience 2009;32(1):1-33.Börner C, Höllt V, Sebald W, Kraus J. Transcriptional regulation of the cannabinoid receptor type 1 gene in T cells by cannabinoids. Journal of leukocyte biology 2007 Jan 1,;81(1):336-343.Boerner C, Bedini A, Hoellt V, Kraus J. Analysis of Promoter Regions Regulating Basal and Interleukin-4-Inducible Expression of the Human CB1 Receptor Gene in T Lymphocytes. Molecular pharmacology 2008 Mar 1,;73(3):1013-1019.McKallip RJ, Nagarkatti M, Nagarkatti PS. Delta-9-tetrahydrocannabinol enhances breast cancer growth and metastasis by suppression of the antitumor immune response. The Journal of immunology (1950) 2005 Mar 15,;174(6):3281-3289.Wang D, Wang H, Ning W, Backlund MG, Dey SK, DuBois RN. Loss of Cannabinoid Receptor 1 Accelerates Intestinal Tumor Growth. Cancer Research 2008 Aug 1,;68(15):6468-6476.Izzo AA, Fezza F, Capasso R, Bisogno T, Pinto L, Iuvone T, et al. Cannabinoid CB1‐receptor mediated regulation of gastrointestinal motility in mice in a model of intestinal inflammation. British journal of pharmacology 2001 Oct;134(3):563-570.Julien B, Grenard P, Teixeira-Clerc F, Van Nhieu JT, Li L, Karsak M, et al. Antifibrogenic role of the cannabinoid receptor CB2 in the liver. Gastroenterology (New York, N.Y. 1943) 2005;128(3):742-755.Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Bátkai S, et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. The Journal of clinical investigation 2005 May;115(5):1298-1305.Jeong W, Osei-Hyiaman D, Park O, Liu J, Bátkai S, Mukhopadhyay P, et al. Paracrine Activation of Hepatic CB1 Receptors by Stellate Cell-Derived Endocannabinoids Mediates Alcoholic Fatty Liver. Cell Metabolism 2008 Mar;7(3):227-235.Kunos G, Osei-Hyiaman D, Liu J, Godlewski G, Bátkai S. Endocannabinoids and the Control of Energy Homeostasis. The Journal of biological chemistry 2008 Nov 28,;283(48):33021-33025.Vickers SP, Webster LJ, Wyatt A, Dourish CT, Kennett GA. Preferential effects of the cannabinoid CB1 receptor antagonist, SR 141716, on food intake and body weight gain of obese (fa/fa) compared to lean Zucker rats. Psychopharmacology 2003 Apr;167(1):103-111.Kim KW, Jo Y, Zhao L, Stallings NR, Chua SC, Parker KL. Steroidogenic Factor 1 Regulates Expression of the Cannabinoid Receptor 1 in the Ventromedial Hypothalamic Nucleus. Molecular endocrinology (Baltimore, Md.) 2008 Aug;22(8):1950-1961.Mach F, Steffens S, Veillard NR, Arnaud C, Pelli G, Burger F, et al. Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature 2005 Apr 7,;434(7034):782-786.Mach F, Steffens S, Veillard NR, Arnaud C, Pelli G, Burger F, et al. Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature 2005 Apr 7,;434(7034):782-786.Hungund BL, Vinod KY, Kassir SA, Basavarajappa BS, Yalamanchili R, Cooper TB, et al. Upregulation of CB1 receptors and agonist-stimulated [35S]GTPgammaS binding in the prefrontal cortex of depressed suicide victims. Molecular psychiatry 2004 Feb;9(2):184-190.Chiu CQ, Puente N, Grandes P, Castillo PE. Dopaminergic Modulation of Endocannabinoid-Mediated Plasticity at GABAergic Synapses in the Prefrontal Cortex. The Journal of neuroscience 2010 May 26,;30(21):7236-7248.Hay EA, Cowie P, Mcewan A, Wilson D, Ross R, Barrett P, et al. Genetic, epigenetic and pharmacological influences modulating tissue specific regulation of the cannabinoid receptor-1 gene (CB1); implications for cannabinoid pharmacogenetics. 2019 Feb 8,.Luo Y, Zhang J, Chen L, Chen S, Chen H, Zhang G, et al. Histone methyltransferase G9a diminishes expression of cannabinoid CB 1 receptors in primary sensory neurons in neuropathic pain. The Journal of biological chemistry 2020 Mar 13,;295(11):3553.Dhopeshwarkar A MK. Functional Selectivity of CB2 Cannabinoid Receptor Ligands at a Canonical and Noncanonical Pathway. J Pharmacol Exp Ther 2016;358(2):342-51.Unal H. Luciferase reporter assay for unlocking ligand-mediated signaling of GPCRs. Methods in Cell Biology. doi:10.1016/bs.mcb.2018.08.001 2018;149:19-30.Nobles KN, Xiao K, Ahn S, Shukla AK, Lam CM, Rajagopal S, et al. Distinct phosphorylation sites on the β(2)-adrenergic receptor establish a barcode that encodes differential functions of β-arrestin. . Sci Signal 2011;4(185):51.Mackie K, Lai Y, Westenbroek R, Mitchell R. Cannabinoids activate an inwardly rectifying potassium conductance and inhibit Q-type calcium currents in AtT20 cells transfected with rat brain cannabinoid receptor. The Journal of neuroscience 1995 Oct 1,;15(10):6552-6561.Haspula D, Clark MA. Cannabinoid Receptors: An Update on Cell Signaling, Pathophysiological Roles and Therapeutic Opportunities in Neurological, Cardiovascular, and Inflammatory Diseases. International journal of molecular sciences 2020 Oct 17,;21(20):7693.Nogueras-Ortiz C, Yudowski GA. The Multiple Waves of Cannabinoid 1 Receptor Signaling. Molecular pharmacology 2016 Nov;90(5):620-626.Delgado-Peraza F, Ahn KH, Nogueras-Ortiz C, Mungrue IN, Mackie K, Kendall DA, Yudowski GA. Mechanisms of Biased β-Arrestin-Mediated Signaling Downstream from the Cannabinoid 1 Receptor. Erratum in: Mol Pharmacol 2016;90(1):62.Nguyen PT, Schmid CL, Raehal KM, Selley DE, Bohn LM, Sim-Selley LJ. β-Arrestin2 Regulates Cannabinoid CB1 Receptor Signaling and Adaptation in a Central Nervous System Region–Dependent Manner. Biological psychiatry (1969) 2012;71(8):714-724.Ahn KH, Mahmoud MM, Shim J, Kendall DA. Distinct Roles of β-Arrestin 1 and β-Arrestin 2 in ORG27569-induced Biased Signaling and Internalization of the Cannabinoid Receptor 1 (CB1). The Journal of biological chemistry 2013 Apr 5,;288(14):9790-9800.Graham ES, Ball N, Scotter EL, Narayan P, Dragunow M, Glass M. Induction of Krox-24 by Endogenous Cannabinoid Type 1 Receptors in Neuro2A Cells Is Mediated by the MEK-ERK MAPK Pathway and Is Suppressed by the Phosphatidylinositol 3-Kinase Pathway. The Journal of biological chemistry 2006 Sep 29,;281(39):29085-29095.Haspula D, Clark MA. MAPK activation patterns of AT1R and CB1R in SHR versus Wistar astrocytes: Evidence of CB1R hypofunction and crosstalk between AT1R and CB1R. Cellular signalling 2017 Dec;40:81-90.Blázquez C, Chiarlone A, Bellocchio L, Resel E, Pruunsild P, García-Rincón D, et al. The CB₁ cannabinoid receptor signals striatal neuroprotection via a PI3K/Akt/mTORC1/BDNF pathway. Cell Death and Differentiation 2015 Oct;22(10):1618-1629.Chanda D, Kim D, Li T, Kim Y, Koo S, Lee C, et al. Cannabinoid Receptor Type 1 (CB1R) Signaling Regulates Hepatic Gluconeogenesis via Induction of Endoplasmic Reticulum-bound Transcription Factor cAMP-responsive Element-binding Protein H (CREBH) in Primary Hepatocytes. The Journal of biological chemistry 2011 Aug 12,;286(32):27971-27979.Bouaboula M, Poinot-Chazel C, Marchand J, Canat X, Bourrié B, Rinaldi-Carmona M, et al. Signaling Pathway Associated with Stimulation of CB2 Peripheral Cannabinoid Receptor. Involvement of Both Mitogen-Activated Protein Kinase and Induction of Krox-24 Expression. European journal of biochemistry 1996 May 1,;237(3):704-711.Nogueras-Ortiz C, Roman-Vendrell C, Mateo-Semidey GE, Liao Y, Kendall DA, Yudowski GA. Retromer stops beta-arrestin 1-mediated signaling from internalized cannabinoid 2 receptors. Molecular Biology of the Cell 2017 Nov 15,;28(24):3554-3561.Lauckner JE, Hille B, Mackie K. The cannabinoid agonist WIN55,212-2 increases intracellular calcium via CB1 receptor coupling to Gq/11 G proteins. Proceedings of the National Academy of Sciences - PNAS 2005 Dec 27,;102(52):19144-19149.Laprairie RB, Bagher AM, Kelly MEM, Dupré DJ, Denovan-Wright EM. Type 1 Cannabinoid Receptor Ligands Display Functional Selectivity in a Cell Culture Model of Striatal Medium Spiny Projection Neurons. The Journal of biological chemistry 2014 Sep 5,;289(36):24845-24862.Navarrete M, Araque A. Endocannabinoids Mediate Neuron-Astrocyte Communication. Neuron (Cambridge, Mass.) 2008;57(6):883-893.Zoratti C, Kipmen‐Korgun D, Osibow K, Malli R, Graier WF. Anandamide initiates Ca2+ signaling via CB2 receptor linked to phospholipase C in calf pulmonary endothelial cells. British journal of pharmacology 2003 Dec;140(8):1351-1362.Kearn CS, Blake-Palmer K, Daniel E, Mackie K, Glass M. Concurrent Stimulation of Cannabinoid CB1 and Dopamine D2 Receptors Enhances Heterodimer Formation: A Mechanism for Receptor Cross-Talk? Molecular pharmacology 2005 May 1,;67(5):1697-1704CARRIBA P, ORTIZ O, CASADO V, CANELA EI, LLUIS C, GOLDBERG SR, et al. Striatal Adenosine A2A and Cannabinoid CB1 Receptors Form Functional Heteromeric Complexes that Mediate the Motor Effects of Cannabinoids. Neuropsychopharmacology (New York, N.Y.) 2007;32(11):2249-2259.Cinar R, Freund Tf, Katona I, Mackie K, Szucs M. Reciprocal inhibition of G-protein signaling is induced by CB1 cannabinoid and GABAB receptor interactions in rat hippocampal membranes. Neurochemistry international 2008;52(8):1402-1409.Rozenfeld R, Gupta A, Gagnidze K, Lim MP, Gomes I, Lee-Ramos D, et al. AT1R-CB1R heteromerization reveals a new mechanism for the pathogenic properties of angiotensin II. The EMBO journal 2011 Jun 15,;30(12):2350-2363.Callén L, Moreno E, Barroso-Chinea P, Moreno-Delgado D, Cortés A, Mallol J, et al. Cannabinoid Receptors CB1 and CB2 Form Functional Heteromers in Brain. The Journal of biological chemistry 2012 Jun 15,;287(25):20851-20865.Turu G, Várnai P, Gyombolai P, Szidonya L, Offertaler L, Bagdy G, et al. Paracrine Transactivation of the CB1 Cannabinoid Receptor by AT1 Angiotensin and Other Gq/11 Protein-coupled Receptors. The Journal of biological chemistry 2009 Jun 19,;284(25):16914-16921.Gyombolai P, Pap D, Turu G, Catt KJ, Bagdy G, Hunyady L. Regulation of endocannabinoid release by G proteins: A paracrine mechanism of G protein-coupled receptor action. Molecular and cellular endocrinology 2012 Apr 28,;353(1-2):29-36.Leterrier C, Bonnard D, Carrel D, Rossier J, Lenkei Z. Constitutive Endocytic Cycle of the CB1 Cannabinoid Receptor. The Journal of biological chemistry 2004 Aug 20,;279(34):36013-36021.Bénard G., Massa F., Puente N., Lourenço J., Bellocchio L., Soria-Gómez E., Matias I., Delamarre A., Metna-Laurent M., Cannich A., et al. Mitochondrial CB1 receptors regulate neuronal energy metabolism-Supplementary information. Nat. Neurosci 2012;15(558–564.).Miller LK, Devi LA. The highs and lows of cannabinoid receptor expression in disease: mechanisms and their therapeutic implications. Pharmacological reviews 2011 Sep;63(3):461-470.Laprairie R, Kelly M, Denovan‐Wright E. The dynamic nature of type 1 cannabinoid receptor (CB1) gene transcription. British journal of pharmacology 2012 Dec;167(8):1583-1595.Mukhopadhyay B, Liu J, Osei-Hyiaman D, Godlewski G, Mukhopadhyay P, Wang L, et al. Transcriptional Regulation of Cannabinoid Receptor-1 Expression in the Liver by Retinoic Acid Acting via Retinoic Acid Receptor-γ. The Journal of biological chemistry 2010 Jun 18,;285(25):19002-19011.Hegyi Z, Oláh T, Kőszeghy Á, Piscitelli F, Holló K, Pál B, et al. CB1 receptor activation induces intracellular Ca2+ mobilization and 2-arachidonoylglycerol release in rodent spinal cord astrocytes. Scientific Reports 2018 Jul 12,;8(1):1-16.Pertwee. Inverse agonism and neutral antagonism at cannabinoid CB1 receptors. Life Sci 2005;76:1307.Patel. et al. Cannabinoid CB1 receptor agonists produce cerebellar dysfunction in mice. J.Pharmacol.Exp.Ther :297-629.Micale et al. The cannabinoid CB1 antagonist TM38837 with limited penetrance to the brain shows reduced fear-promoting effects in mice. Front.Pharmacol 2019;10.German et al. Diarylureas as allosteric modulators of the cannabinoid CB1 receptor: structure-activity relationship studies on 1-(4-chlorophenyl)-3-{3-[6-(pyrrolidin-1-yl)pyridin-2-yl]phenyl}urea (PSNCBAM-1). . J.Med.Chem. 2014;57.Laprairie RB, Bagher AM, Kelly ME, Denovan-Wright EM. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol. 2015;172(20):4790-4805.Manera et al. Design, synthesis, and biological evaluation of new 1,8-naphthyridin-4(1H)-on-3-carboxamide and quinolin-4(1H)-on-3-carboxamide derivatives as CB2 selective agonists. J.Med.Chem ;49:5947.Pasquini et al. Investigations on the 4-quinolone-3-carboxylic acid motif. 2. Synthesis and structure-activity relationship of potent and selective cannabinoid-2 receptor agonists endowed with analgesic activity in vivo. J.Med.Chem ;51:5075.Gado et al. Identification of the first synthetic allosteric modulator of the CB2 receptors and evidence of its efficacy for neuropathic pain relief. J.Med.Chem 2019;62:276.Smith JS, Lefkowitz RJ, Rajagopal S. Biased signalling: from simple switches to allosteric microprocessors. Nat Rev Drug Discov. 2018 Apr;17(4):243-260. . 2018;17(4):243-260.Samama P, Cotecchia S, Costa T, Lefkowitz RJ. A mutation-induced activated state of the beta 2-adrenergic receptor. Extending the ternary complex model. The Journal of biological chemistry 1993 Mar 5,;268(7):4625-4636.Changeux J, Edelstein SJ. Allosteric Mechanisms of Signal Transduction. Science 2005 Jun 3,;308(5727):1424-1428.Kjelsberg MA, Cotecchia S, Ostrowski J, Caron MG, Lefkowitz RJ. Constitutive activation of the alpha 1B-adrenergic receptor by all amino acid substitutions at a single site. Evidence for a region which constrains receptor activation. The Journal of biological chemistry 1992 Jan 25,;267(3):1430-1433.Chen X, Bai B, Tian Y, Du H, Chen J. Identification of Serine 348 on the Apelin Receptor as a Novel Regulatory Phosphorylation Site in Apelin-13-induced G Protein-independent Biased Signaling. The Journal of biological chemistry 2014 Nov 7,;289(45):31173-31187.Wanka L, Babilon S, Burkert K, Mörl K, Gurevich VV, Beck-Sickinger AG. C-terminal motif of human neuropeptide Y4 receptor determines internalization and arrestin recruitment. Cellular signalling 2017 Jan;29:233-239.Zidar DA, Violin JD, Whalen EJ, Lefkowitz RJ. Selective Engagement of G Protein Coupled Receptor Kinases (GRKs) Encodes Distinct Functions of Biased Ligands. Proceedings of the National Academy of Sciences - PNAS 2009 Jun 16,;106(24):9649-9654.Urs NM, Gee SM, Pack TF, McCorvy JD, Evron T, Snyder JC, et al. Distinct cortical and striatal actions of a β-arrestin–biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties. Proceedings of the National Academy of Sciences - PNAS 2016 Dec 13,;113(50):E8178-E8186.Navarro G, Reyes-Resina I, Rivas-Santisteban R, Sánchez de Medina V, Morales P. Cannabidiol skews biased agonism at cannabinoid CB1 and CB2 receptors with smaller effect in CB1-CB2 heteroreceptor complexes. Biochem Pharmacol 2018;157:148-158.Maayah ZH, Takahara S, Ferdaoussi M, Dyck JRB. The molecular mechanisms that underpin the biological benefits of full-spectrum cannabis extract in the treatment of neuropathic pain and inflammation. Biochim Biophys Acta Mol Basis Dis 2020;1866(7):165771.P. Pacher, S. Batkai, G. Kunos. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol. Rev. 2006;58:389–462.A. Bilkei-Gorzo, O. Albayram, A. Draffehn, K. Michel, A. Piyanova, H. Oppenheimer. A chronic low dose of Delta(9)-tetrahydrocannabinol (THC) restores cognitive function in old mice. Nat. Med 2017;23:782–787.C. Ibeas Bih, T. Chen, A.V. Nunn, M. Bazelot, M. Dallas, B.J. Whalley. Molecular targets of Cannabidiol in neurological disorders, Neurotherapeutics. The Journal of the American Society for Experimental NeuroTherapeutics 2015;12:699–730.P. Seeman. Cannabidiol is a partial agonist at dopamine D2High receptors, predicting its antipsychotic clinical dose. Transl. Psychiatry 2016;6:920.F.V. Gomes, L.B. Resstel, F.S. Guimaraes. The anxiolytic-like effects of cannabidiol injected into the bed nucleus of the stria terminalis are mediated by 5-HT1A receptors. Psychopharmacology 2011;213:465–473.L. De Petrocellis, A. Ligresti, A.S. Moriello, M. Allara, T. Bisogno, S. Petrosino, C.G. Stott, V. Di Marzo. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Pharmacol. 2011;163:1479–1494.Ruhaak LR, Felth J, Karlsson PC, Rafter JJ, Verpoorte R, Bohlin L, 34(5):774-8. Evaluation of the cyclooxygenase inhibiting effects of six major cannabinoids isolated from Cannabis sativa. Biol Pharm Bull. 2011;34(5):774-8. 2011;34(5):774-778.DeLong GT, Wolf CE, Poklis A, Lichtman AH. Pharmacological evaluation of the natural constituent of Cannabis sativa, cannabichromene and its modulation by Δ(9)-tetrahydrocannabinol. Drug and alcohol dependence 2010 Nov 1,;112(1-2):126-133.Cascio MG, Gauson LA, Stevenson LA, Ross RA, Pertwee RG. Evidence that the plant cannabinoid cannabigerol is a highly potent alpha2-adrenoceptor agonist and moderately potent 5HT1A receptor antagonist. British journal of pharmacology 2010 Jan;159(1):129-141.Comelli F, Giagnoni G, Bettoni I, Colleoni M, Costa B. Antihyperalgesic effect of a Cannabis sativa extract in a rat model of neuropathic pain: mechanisms involved. Phytotherapy research 2008 Aug;22(8):1017-1024.Miyazawa M, Yamafuji C. Inhibition of Acetylcholinesterase Activity by Bicyclic Monoterpenoids. Journal of agricultural and food chemistry 2005 Mar 9,;53(5):1765-1768.Klauke A-, Racz I, Pradier B, Markert A, Zimmer AM, Gertsch J, et al. The cannabinoid CB.sub.2 receptor-selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain. European neuropsychopharmacology 2014 Apr 1,;24(4):608.Alberti TB, Barbosa WLR, Vieira JLF, Raposo NRB, Dutra RC. (−)-β-Caryophyllene, a CB2 Receptor-Selective Phytocannabinoid, Suppresses Motor Paralysis and Neuroinflammation in a Murine Model of Multiple Sclerosis. International journal of molecular sciences 2017 Apr 1,;18(4):691.Kim HJ, Kim B, Park BM, Jeon JE, Lee SH, Mann S, et al. Topical cannabinoid receptor 1 agonist attenuates the cutaneous inflammatory responses in oxazolone-induced atopic dermatitis model. International journal of dermatology 2015 Oct;54(10):e401-e408.Maresz K, Carrier EJ, Ponomarev ED, Hillard CJ, Dittel BN. Modulation of the cannabinoid CB2 receptor in microglial cells in response to inflammatory stimuli. Journal of neurochemistry 2005 Oct;95(2):437-445. (109) Galán-Ganga M, del Río R, Jiménez-Moreno N, Díaz-Guerra M, Lastres-Becker I. Cannabinoid CB2 Receptor Modulation by the Transcription Factor NRF2 is Specific in Microglial Cells. Cellular and molecular neurobiology 2020 Jan 1,;40(1):167-177.Gaffal E, Cron M, Glodde N, Tüting T. Anti‐inflammatory activity of topical THC in DNFB‐mediated mouse allergic contact dermatitis independent of CB1 and CB2 receptors. Allergy (Copenhagen) 2013 Aug;68(8):994-1000.Philpott HT, OʼBrien M, McDougall JJ. Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis. Pain (Amsterdam) 2017 Dec;158(12):2442-2451.Schuelert N, McDougall JJ. Cannabinoid‐mediated antinociception is enhanced in rat osteoarthritic knees. Arthritis and rheumatism 2008 Jan;58(1):145-153.Romero V, Lara JR, Otero-Espinar F, Salgado MH, Modolo NSP, Barros, Guilherme Antonio Moreira de. Capsaicin topical cream (8%) for the treatment of myofascial pain syndrome. Revista brasileira de anestesiologia 2019 Sep;69(5):432-438.Xu DH, Cullen BD, Tang M, Fang Y. The Effectiveness of Topical Cannabidiol Oil in Symptomatic Relief of Peripheral Neuropathy of the Lower Extremities. Current pharmaceutical biotechnology 2020;21(5):390-402.Nitecka-Buchta A, Nowak-Wachol A, Wachol K, Walczyńska-Dragon K, Olczyk P, Batoryna O, et al. Myorelaxant Effect of Transdermal Cannabidiol Application in Patients with TMD: A Randomized, Double-Blind Trial. Journal of clinical medicine 2019 Nov 6,;8(11):1886.García-Andreu J. Manejo básico del dolor agudo y crónico. Anest Méx 2017;29:77-85.Julius D, Allan I. Molecular mechanisms of nociception. Nature 2001;413:203-210.Solé-Magdalena A, Revuelta EG, Menénez-Díaz I, Calavia MG, et al. Human odontoblasts express transient receptor protein and acid-sensing ion channel mechanosensor proteins. Microsc Res Tech 2011;74(5):457-63.Smith PC, Martínez C, Martínez J, McCulloch CA. Role of Fibroblast Populations in Periodontal Wound Healing and Tissue Remodeling. Front Physiol 2019;10:270.Haspula D, Clark MA. Cannabinoid Receptors: An Update on Cell Signaling, Pathophysiological Roles and Therapeutic Opportunities in Neurological, Cardiovascular, and Inflammatory Diseases. Int J Mol Sci 2020;21(20):7693.Philpott HT, OʼBrien M, McDougall JJ. Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis. Pain 2017;158(12):2442-2451.Konermann A, Jäger A, Held SAE, Brossart P, et al. In vivo and In vitro Identification of Endocannabinoid Signaling in Periodontal Tissues and Their Potential Role in Local Pathophysiology. Cell Mol Neurobiol 2017;37(8):1511-1520.Qian H, Zhao Y, Peng Y, Han C, et al. Activation of cannabinoid receptor CB2 regulates osteogenic and osteoclastogenic gene expression in human periodontal ligament cells. J Periodontal Res 2010; 45(4):504-11.Ossola CA, Surkin PN, Mohn CE, Elverdin JC, et al. Anti-Inflammatory and Osteoprotective Effects of Cannabinoid-2 Receptor Agonist HU-308 in a Rat Model of Lipopolysaccharide-Induced Periodontitis. J Periodontol 2016;87(6):725-34.Picciolo G, Pallio G, Altavilla D, Vaccaro M, et al. β-Caryophyllene Reduces the Inflammatory Phenotype of Periodontal Cells by Targeting CB2 Receptors. Biomedicines 2020;8(6):164Schefe JH, Lehmann KE, Buschmann IR, Unger T, et al. Quantitative real-time RT-PCR data analysis: current concepts and the novel gene expression's CT difference formula. J Mol Med 2006;84(11):901-910.Beneng K, Renton T, Yilmaz Z, Yiangou Y, et al. Cannabinoid receptor CB1-immunoreactive nerve fibres in painful and non-painful human tooth pulp. J Clin Neurosci 2010;17(11):1476–1479.Somsak M, Sopee P, Pornpoj F. Cannabinoid receptor 1 (CB1R) expression in rat dental pulp. Oral Sci Int 2012;9(1):17-20.Prada-Arismendy J, Castellanos JE. Real time PCR. Application in dengue studies. Colombia médica (Cali, Colombia) 2011 Jun 6,;42(2):243-258.Köhsler M, Leitsch D, Müller N, Walochnik J. Validation of reference genes for the normalization of RT-qPCR gene expression in Acanthamoeba spp. Scientific reports 2020 Jun 25,;10(1):10362.Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M, et al. The MIQE Guidelines: Minimum Information for Publication of Quantitative Real-Time PCR Experiments. Clinical chemistry (Baltimore, Md.) 2009 Apr 1,;55(4):611-622.Romero Geraldo R, Hernández Saavedra N, Fimbres Olivarría D, García Lagunas N. Validation of suitable reference genes for quantitative real-time PCR normalization in Crassostrea gigas spat stage during toxic dinoflagellates exposure. Biotecnia 2020;22(2):94-102.Dheda K, Huggett JF, Bustin SA, Johnson MA, Rook G, ZumLa A. Validation of housekeeping genes for normalizing RNA expression in real-time PCR. BioTechniques 2004 Jul 1,;37(1):112-119.Suzuki T, Higgins PJ, Crawford DR. Control Selection for RNA Quantitation. BioTechniques 2000 Aug 1,;29(2):332-337.Chapman JR, Waldenström J. With Reference to Reference Genes: A systematic review of endogenous controls in gene expression studies. PloS one 2015;10(11):e0141853.Hruz T, Wyss M, Docquier M, Pfaffl MW, Masanetz S, Borghi L, et al. RefGenes: identification of reliable and condition specific reference genes for RT-qPCR data normalization. BMC genomics 2011 Mar 21,;12(1):156.Ito S, Gojoubori T, Tsunoda K, Yamaguchi Y, Asano M, Goke E, et al. Nicotine-induced expression of low-density lipoprotein receptor in oral epithelial cells. PLoS ONE 2013;8(12):e82563.Ockenga W, Kühne S, Bocksberger S, Banning A, Tikkanen R. Epidermal growth factor receptor transactivation is required for mitogen-activated protein kinase activation by muscarinic acetylcholine receptors in HaCaT keratinocytes. International Journal of Molecular Sciences 2014 Nov 21,;15(11):21433-21454.Graeser A, Huebbe P, Storm N, Höppner W, Döring F, Wagner AE, et al. Apolipoprotein E genotype affects tissue metallothionein levels: studies in targeted gene replacement mice. Genes & nutrition 2012 Apr;7(2):247-255.Zheng X, Rao X, Gomez-Gutierrez JG, Hao H, McMasters KM, Zhou HS. Adenovirus E1B55K Region Is Required To Enhance Cyclin E Expression for Efficient Viral DNA Replication. Journal of Virology 2008 Apr 1,;82(7):3415-3427.Vuong HG, Kondo T, Oishi N, Nakazawa T, Mochizuki K, Miyauchi A, et al. Paediatric follicular thyroid carcinoma – indolent cancer with low prevalence of RAS mutations and absence of PAX8–PPARG fusion in a Japanese population. Histopathology 2017 Nov;71(5):760-768.Nikiforova MN, Biddinger PW, Caudill CM, Kroll TG, Nikiforov YE. PAX8-PPARgamma rearrangement in thyroid tumors: RT-PCR and immunohistochemical analyses. The American journal of surgical pathology 2002 Aug;26(8):1016-1023.Lim H, Nam OH, Kim M, El-Fiqi A, Yun H, Lee Y, et al. Delivery of dexamethasone from bioactive nanofiber matrices stimulates odontogenesis of human dental pulp cells through integrin/BMP/mTOR signaling pathways. International Journal of Nanomedicine 2016;11:2557-2567.Mar JC, Kimura Y, Schroder K, Irvine KM, Hayashizaki Y, Suzuki H, et al. Data-driven normalization strategies for high-throughput quantitative RT-PCR. BMC Bioinformatics 2009 Apr 19,;10(1):110.Pfaffl M, Tichopad A, Prgomet C, Neuvians T. Determination of stable housekeeping genes, differentially regulated target genes and sample integrity: BestKeeper – Excel-based tool using pair-wise correlations. Biotechnology Letters 2004 Mar;26(6):509-515.Maresz K, Carrier EJ, Ponomarev ED, Hillard CJ, Dittel BN. Modulation of the cannabinoid CB2 receptor in microglial cells in response to inflammatory stimuli. Journal of neurochemistry 2005 Oct;95(2):437-445.Nakajima Y, Furuichi Y, Biswas KK, Hashiguchi T, et al. Endocannabinoid, anandamide in gingival tissue regulates the periodontal inflammation through NF-kappaB pathway inhibition. FEBS Lett 2006;580(2):613-9.Ibeas C, Chen T, Nunn VM, Bazelot, et al. Molecular targets of Cannabidiol in neurological disorders, Neurotherapeutics. NeuroTherapeutics 2015;12:699–730.Seeman P. Cannabidiol is a partial agonist at dopamine D2High receptors, predicting its antipsychotic clinical dose. Transl Psychiatry 2016;6:920.Gomes FV, Resstel LB, Guimaraes FS. The anxiolytic-like effects of cannabidiol injected into the bed nucleus of the stria terminalis are mediated by 5-HT1A receptors. Psychopharmacology 2011;213:465–473.De Petrocellis L, Ligresti A, Moriello AS, Allara M, et al. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Pharmacol 2011;163:1479–1494.Ruhaak LR, Felth J, Karlsson PC, Rafter JJ. Evaluation of the cyclooxygenase inhibiting effects of six major cannabinoids isolated from Cannabis sativa. Biol Pharm Bull 2011;34(5):774-8de Almeida DL, Devi LA. Diversity of molecular targets and signaling pathways for CBD. Pharmacol Res Perspect 2020;8(6).Kassebaum NJ, Bernabé E, Dahiya M, Bhandari B, Murray CJL, Marcenes W. Global Burden of Untreated Caries. Journal of Dental Research 2015 May;94(5):650-658Hossain MZ, Bakri MM, Yahya F, Ando H, Unno S, Kitagawa J. The role of transient receptor potential (TRP) channels in the transduction of dental pain. International Journal of Molecular Sciences 2019 Jan 27,;20(3):526.Pergolizzi JV, Magnusson P, LeQuang JA, Gharibo C, Varrassi G. The pharmacological management of dental pain. Expert opinion on pharmacotherapy 2020 Mar 23,;21(5):591-601.Julius D AI. Molecular mechanisms of nociception. Nature 2001;413:203-210.Ardila.C.M. Hipersensibilidad dentinal: Una revisión de su etiología, patogénesis y tratamiento. Av Odontoestomatol . 2009;25:137-146.Shibukawa Y, Sato M, Kimura M, Sobhan U, Shimada M, Nishiyama A, et al. Odontoblasts as sensory receptors: transient receptor potential channels, pannexin-1, and ionotropic ATP receptors mediate intercellular odontoblast-neuron signal transduction. Pflugers Arch. 2015;467(4):843-463Munt ea. THC and Cannabinol Activate Sensory Nerves. J. Neurosci 2002;22(11):4720–4727M. L. Velandia, J. V. Montoya, M. Martínez, S. Perdomo, and J. E. Castellanos. Comparison of three neuro-tracing techniques for identification of the sciatic spinal nerve origin in mice. Biomédica 2002;22(4):529–534Thermo Fisher. Electrofisiology protocol. Available at: https://www.thermofisher.com/co/en/home/references/protocols/neurobiology/neurobiology-protocols/electrophysiology.htmL.Farges J, Carrouel F, Keller J, Baudouin C, Msika P, Bleicher F, et al. Cytokine production by human odontoblast-like cells upon Toll-like receptor-2 engagement. Immunobiology (1979) 2010;216(4):513-517.Pääkkönen V, Rusanen P, Hagström J, Tjäderhane L. Mature human odontoblasts express virus-recognizing toll-like receptors. International endodontic journal 2014 Oct;47(10):934-941.Botero TM, Shelburne CE, Holland GR, Hanks CT, Nör JE. TLR4 Mediates LPS-Induced VEGF Expression in Odontoblasts. Journal of endodontics 2006;32(10):951-955.Kawasaki Takumi, Kawai Taro. Toll-like receptor signaling pathways. Front. Immunol 2014 25 September.Caviedes-Bucheli, Javier, DDS, MSc, Muñoz, Hugo Roberto, DDS, MSc, Azuero-Holguín MM, DDS, Ulate E, DDS. Neuropeptides in Dental Pulp: The Silent Protagonists. Journal of endodontics 2008;34(7):773-788McCoy KL. Interaction between Cannabinoid System and Toll-Like Receptors Controls Inflammation. Mediators of Inflammation 2016 Aug 11,;2016:5831315-18.Allard B, Magloire H, Couble ML, Maurin JC, Bleicher F. Voltage-gated sodium channels confer excitability to human odontoblasts: possible role in tooth pain transmission. J Biol Chem. 2013;281(39):29002-290010.Caviedes-Bucheli J, Gutierrez-Guerra JE, Salazar F, Pichardo D, Moreno GC, Munoz HR. Substance P receptor expression in healthy and inflamed human pulp tissue. International endodontic journal 2007 Feb;40(2):106-111.Darmani NA, Belkacemi L, Zhong W. Δ9-THC and related cannabinoids suppress substance P- induced neurokinin NK1-receptor-mediated vomiting via activation of cannabinoid CB1 receptor. European journal of pharmacology 2019 Dec 15,;865:172806Oshita K, Inoue A, Tang H, Nakata Y, Kawamoto M, Yuge O. CB1 Cannabinoid Receptor Stimulation Modulates Transient Receptor Potential Vanilloid Receptor 1 Activities in Calcium Influx and Substance P Release in Cultured Rat Dorsal Root Ganglion Cells. Journal of Pharmacological Sciences 2005;97(3):377-385.Kibret BG, Ishiguro H, Horiuchi Y, Onaivi ES. New Insights and Potential Therapeutic Targeting of CB2 Cannabinoid Receptors in CNS Disorders. International journal of molecular sciences 2022 Jan 17,;23(2):975.Shohami E, Cohen‐Yeshurun A, Magid L, Algali M, Mechoulam R. Endocannabinoids and traumatic brain injury. British journal of pharmacology 2011 Aug;163(7):1402-1410Patil M, Patwardhan A, Salas MM, Hargreaves KM, Akopian AN. Cannabinoid receptor antagonists AM251 and AM630 activate TRPA1 in sensory neurons. Neuropharmacology 2011;61(4):778-788Bakali E, Tincello D. Current Understanding of Cannabinoids and Detrusor Overactivity. Curr Bladder Dysfunct Rep 2017 Mar 7,;12(1):86-94.Biominerales PharmaInvestigadoresORIGINALDocumento tesis Laura M Navarro-Saiz.pdfDocumento tesis Laura M Navarro-Saiz.pdfTesis de Maestría en Odontologíaapplication/pdf1068094https://repositorio.unal.edu.co/bitstream/unal/81731/1/Documento%20tesis%20Laura%20M%20Navarro-Saiz.pdf9da7f5c95614db989462f2ebd9dc6a4dMD51LICENSElicense.txtlicense.txttext/plain; charset=utf-84074https://repositorio.unal.edu.co/bitstream/unal/81731/2/license.txt8153f7789df02f0a4c9e079953658ab2MD52THUMBNAILDocumento tesis Laura M Navarro-Saiz.pdf.jpgDocumento tesis Laura M Navarro-Saiz.pdf.jpgGenerated Thumbnailimage/jpeg3774https://repositorio.unal.edu.co/bitstream/unal/81731/3/Documento%20tesis%20Laura%20M%20Navarro-Saiz.pdf.jpg1c056af1cae4b2d718de586b3d3dca7bMD53unal/81731oai:repositorio.unal.edu.co:unal/817312023-08-06 23:03:41.569Repositorio Institucional Universidad Nacional de Colombiarepositorio_nal@unal.edu.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

Evaluación de la presencia y actividad de receptores cannabinoides en pulpa dental y odontoblastos humanos

Publicaciones similares