The Endocannabinoid System Alleviates Pain in a Murine Model of Cancer-Induced Bone Pain.

Animals Bone Neoplasms / physiopathology Cancer Pain / drug therapy Carbamates / therapeutic use Cell Line, Tumor Disease Models, Animal Dose-Response Relationship, Drug Endocannabinoids / physiology Female Mammary Neoplasms, Experimental / pathology Mice Mice, Inbred BALB C Monoacylglycerol Lipases / antagonists & inhibitors Receptor, Cannabinoid, CB1 / physiology Receptor, Cannabinoid, CB2 / physiology Succinimides / therapeutic use

Journal

The Journal of pharmacology and experimental therapeutics
ISSN: 1521-0103
Titre abrégé: J Pharmacol Exp Ther
Pays: United States
ID NLM: 0376362

Informations de publication

Date de publication:
05 2020
Historique:
received: 27 09 2019
accepted: 10 02 2020
pubmed: 15 2 2020
medline: 9 9 2020
entrez: 15 2 2020
Statut: ppublish

Résumé

Metastatic breast cancer is prevalent worldwide, and one of the most common sites of metastasis is long bones. Of patients with disease, the major symptom is pain, yet current medications fail to adequately result in analgesic efficacy and present major undesirable adverse effects. In our study, we investigate the potential of a novel monoacylglycerol lipase (MAGL) inhibitor, MJN110, in a murine model of cancer-induced bone pain. Literature has previously demonstrated that MAGL inhibitors function to increase the endogenous concentrations of 2-arachydonylglycerol, which then activates CB1 and CB2 receptors to inhibit inflammation and pain. We demonstrate that administration of MJN110 significantly and dose dependently alleviates spontaneous pain behavior during acute administration compared with vehicle control. In addition, MJN110 maintains its efficacy in a chronic-dosing paradigm over the course of 7 days without signs of receptor sensitization. In vitro analysis of MJN110 demonstrated a dose-dependent and significant decrease in cell viability and proliferation of 66.1 breast adenocarcinoma cells to a greater extent than KML29, an alternate MAGL inhibitor, or the CB2 agonist JWH015. Chronic administration of the compound did not appear to affect tumor burden, as evidenced by radiograph or histologic analysis. Together, these data support the application for MJN110 as a novel therapeutic for cancer-induced bone pain. SIGNIFICANCE STATEMENT: Current standard of care for metastatic breast cancer pain is opioid-based therapies with adjunctive chemotherapy, which have highly addictive and other deleterious side effects. The need for effective, non-opioid-based therapies is essential, and harnessing the endogenous cannabinoid system is proving to be a new target to treat various types of pain conditions. We present a novel drug targeting the endogenous cannabinoid system that is effective at reducing pain in a mouse model of metastatic breast cancer to bone.

Identifiants

DOI: 10.1124/jpet.119.262337 PMID: 32054717 PMC: PMC7160863
pubmed: 32054717
pii: jpet.119.262337
doi: 10.1124/jpet.119.262337
pmc: PMC7160863
doi:

Substances chimiques

Carbamates 0
Endocannabinoids 0
MJN110 0
Receptor, Cannabinoid, CB1 0
Receptor, Cannabinoid, CB2 0
Succinimides 0
Monoacylglycerol Lipases EC 3.1.1.23

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

230-238

Subventions

Organisme : NIDA NIH HHS
ID : P01 DA041307
Pays : United States
Organisme : NIH HHS
ID : S10 OD025279
Pays : United States
Organisme : NIH HHS
ID : S10 OD026857
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA033760
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA142115
Pays : United States

Informations de copyright

Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.

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Auteurs

A L Thompson (AL)

Department of Medical Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona (A.L.T., S.A.G., H.A.C., N.B., T.M.L.-M., T.W.V); Division of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland (S.A.G.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (M.J.N., B.F.C.).

S A Grenald (SA)

Department of Medical Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona (A.L.T., S.A.G., H.A.C., N.B., T.M.L.-M., T.W.V); Division of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland (S.A.G.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (M.J.N., B.F.C.).

H A Ciccone (HA)

Department of Medical Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona (A.L.T., S.A.G., H.A.C., N.B., T.M.L.-M., T.W.V); Division of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland (S.A.G.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (M.J.N., B.F.C.).

N BassiriRad (N)

Department of Medical Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona (A.L.T., S.A.G., H.A.C., N.B., T.M.L.-M., T.W.V); Division of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland (S.A.G.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (M.J.N., B.F.C.).

M J Niphakis (MJ)

Department of Medical Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona (A.L.T., S.A.G., H.A.C., N.B., T.M.L.-M., T.W.V); Division of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland (S.A.G.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (M.J.N., B.F.C.).

B F Cravatt (BF)

Department of Medical Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona (A.L.T., S.A.G., H.A.C., N.B., T.M.L.-M., T.W.V); Division of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland (S.A.G.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (M.J.N., B.F.C.).

T M Largent-Milnes (TM)

Department of Medical Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona (A.L.T., S.A.G., H.A.C., N.B., T.M.L.-M., T.W.V); Division of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland (S.A.G.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (M.J.N., B.F.C.).

T W Vanderah (TW)

Department of Medical Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona (A.L.T., S.A.G., H.A.C., N.B., T.M.L.-M., T.W.V); Division of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland (S.A.G.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (M.J.N., B.F.C.) vanderah@email.arizona.edu.

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Classifications MeSH

Recherchemedicale.com › Eucaryotes › Animaux › The Endocannabinoid System Alleviates Pain in...
Recherchemedicale.com › Maladies ostéomusculaires › Maladies osseuses › Tumeurs osseuses › The Endocannabinoid System Alleviates Pain in...
Recherchemedicale.com › États, signes et symptômes pathologiques › Signes et symptômes › Manifestations neurologiques › Douleur cancéreuse › The Endocannabinoid System Alleviates Pain in...
Recherchemedicale.com › Composés chimiques organiques › Acides carboxyliques › Acides acycliques › Carbamates › The Endocannabinoid System Alleviates Pain in...
Recherchemedicale.com › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › The Endocannabinoid System Alleviates Pain in...
Recherchemedicale.com › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › The Endocannabinoid System Alleviates Pain in...
Recherchemedicale.com › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes toxicologiques › Relation dose-effet des médicaments › The Endocannabinoid System Alleviates Pain in...
Recherchemedicale.com › Lipides › Acides gras › Endocannabinoïdes › The Endocannabinoid System Alleviates Pain in...
Recherchemedicale.com › Techniques d'investigation › Modèles animaux › Tumeurs expérimentales › Tumeurs expérimentales de la mamelle › The Endocannabinoid System Alleviates Pain in...
Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › The Endocannabinoid System Alleviates Pain in...
Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée BALB C › The Endocannabinoid System Alleviates Pain in...
Recherchemedicale.com › Enzymes et coenzymes › Enzymes › Hydrolases › Esterases › Carboxylic ester hydrolases › Acylglycerol lipase › The Endocannabinoid System Alleviates Pain in...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs couplés aux protéines G › Récepteurs de cannabinoïdes › Récepteur cannabinoïde de type CB1 › The Endocannabinoid System Alleviates Pain in...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs couplés aux protéines G › Récepteurs de cannabinoïdes › Récepteur cannabinoïde de type CB2 › The Endocannabinoid System Alleviates Pain in...
Recherchemedicale.com › Composés hétérocycliques › Composés hétéromonocycliques › Pyrrolidines › Pyrrolidones › Succinimides › The Endocannabinoid System Alleviates Pain in...