title: Role of the endocannabinoid system in the emotional manifestations of osteoarthritis pain.
abstract: In this study, we investigated the role of the endocannabinoid system (ECS) in the emotional and cognitive alterations associated with osteoarthritis pain. The monosodium iodoacetate model was used to evaluate the affective and cognitive manifestations of osteoarthritis pain in type 1 (CB1R) and type 2 (CB2R) cannabinoid receptor knockout and wild-type mice and the ability of CB1R (ACEA) and CB2R (JWH133) selective agonists to improve these manifestations during a 3-week time period. The levels of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were measured in plasma and brain areas involved in the control of these manifestations. Patients with knee osteoarthritis and healthy controls were recruited to evaluate pain, affective, and cognitive symptoms, as well as plasma endocannabinoid levels and cannabinoid receptor gene expression in peripheral blood lymphocytes. The affective manifestations of osteoarthritis were enhanced in CB1R knockout mice and absent in CB2R knockouts. Interestingly, both ACEA and JWH133 ameliorated the nociceptive and affective alterations, whereas ACEA also improved the associated memory impairment. An increase of 2-AG levels in prefrontal cortex and plasma was observed in this mouse model of osteoarthritis. In agreement, an increase of 2-AG plasmatic levels and an upregulation of CB1R and CB2R gene expression in peripheral blood lymphocytes were observed in patients with osteoarthritis compared with healthy subjects. Changes found in these biomarkers of the ECS correlated with pain, affective, and cognitive symptoms in these patients. The ECS plays a crucial role in osteoarthritis and represents an interesting pharmacological target and biomarker of this disease.
authors.affiliation: Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Pompeu Fabra University (CEXS-UPF), Barcelona, Spain Department of Experimental and Health Sciences, Pompeu Fabra University (CEXS-UPF), Barcelona, Spain Cell Research Group on Inflammation and Cartilage, Hospital del Mar Medical Research Institute, Rheumatology Department, Hospital del Mar, Barcelona, Spain Human Pharmacology and Clinical Neurosciences Research Group, Neuroscience Research Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain Department of Pharmacology, School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Alicante, Spain CIBER de Fisiopatología Obesidad y Nutrición, Santiago de Compostela, Spain Department of Rheumatology, Universitat Autònoma de Barcelona, Hospital del Mar, Barcelona, Spain (A. S. Bura is now with the Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, München, Germany).
authors.forename: Carmen
authors.initials: C
authors.lastname: La Porta
authors.forename: S Andreea
authors.initials: SA
authors.lastname: Bura
authors.forename: Jone
authors.initials: J
authors.lastname: Llorente-Onaindia
authors.forename: Antoni
authors.initials: A
authors.lastname: Pastor
authors.forename: Francisco
authors.initials: F
authors.lastname: Navarrete
authors.forename: María Salud
authors.initials: MS
authors.lastname: García-Gutiérrez
authors.forename: Rafael
authors.initials: R
authors.lastname: De la Torre
authors.forename: Jorge
authors.initials: J
authors.lastname: Manzanares
authors.forename: Jordi
authors.initials: J
authors.lastname: Monfort
authors.forename: Rafael
authors.initials: R
authors.lastname: Maldonado
mesh_terms: D000368:Aged; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism / Q000627:therapeutic use; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology*; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D063388:Endocannabinoids / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000633:toxicity; D005260:Female; D005989:Glycerides / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D007461:Iodoacetates / Q000633:toxicity; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D019964:Mood Disorders / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics; D010003:Osteoarthritis / Q000139:chemically induced / Q000150:complications* / Q000235:genetics; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000172:deficiency / Q000235:genetics; D043885:Receptor, Cannabinoid, CB2 / Q000172:deficiency / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005989:Glycerides; D007461:Iodoacetates; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D011965:Receptors, Glucocorticoid; C094503:glyceryl 2-arachidonate; D003346:Corticotropin-Releasing Hormone