{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T11:58:12Z","timestamp":1790855892165,"version":"4.1.0"},"reference-count":54,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2020,10,6]],"date-time":"2020-10-06T00:00:00Z","timestamp":1601942400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["UMO-2014\/13\/B\/NZ7\/02311"],"award-info":[{"award-number":["UMO-2014\/13\/B\/NZ7\/02311"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["UMO-2012\/07\/E\/NZ7\/01269"],"award-info":[{"award-number":["UMO-2012\/07\/E\/NZ7\/01269"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Osteoarthritis (OA) is a degenerative joint disease manifested by movement limitations and chronic pain. Endocannabinoid system (ECS) may modulate nociception via cannabinoid and TRPV1 receptors. The purpose of our study was to examine alterations in the spinal and joint endocannabinoid system during pain development in an animal model of OA. Wistar rats received intra-articular injection of 3mg of sodium monoiodoacetate (MIA) into the knee joint. Animals were sacrificed on day 2, 7, 14, 21, 28 after injection and lumbar spinal cord, cartilage and synovium were collected. Changes in the transcription levels of the ECS elements were measured. At the spinal level, gene expression levels of the cannabinoid and TRPV1 receptors as well as enzymes involved in anandamide synthesis and degradation were elevated in the advanced OA phase. In the joint, an important role of the synovium was demonstrated, since cartilage degeneration resulted in attenuation of the changes in the gene expression. Enzymes responsible for anandamide synthesis and degradation were upregulated particularly in the early stages of OA, presumably in response to early local joint inflammation. The presented study provides missing information about the MIA-induced OA model and encourages the development of a therapy focused on the molecular role of ECS.<\/jats:p>","DOI":"10.3390\/ijms21197381","type":"journal-article","created":{"date-parts":[[2020,10,7]],"date-time":"2020-10-07T09:12:58Z","timestamp":1602061978000},"page":"7381","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Alterations in Anandamide Synthesis and Degradation during Osteoarthritis Progression in an Animal Model"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6980-8273","authenticated-orcid":false,"given":"Marta","family":"Bryk","sequence":"first","affiliation":[{"name":"Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343 Cracow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6803-4915","authenticated-orcid":false,"given":"Jakub","family":"Chwastek","sequence":"additional","affiliation":[{"name":"Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343 Cracow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3395-5191","authenticated-orcid":false,"given":"Magdalena","family":"Kostrzewa","sequence":"additional","affiliation":[{"name":"Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343 Cracow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4102-7245","authenticated-orcid":false,"given":"Jakub","family":"Mlost","sequence":"additional","affiliation":[{"name":"Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343 Cracow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"P\u0119dracka","sequence":"additional","affiliation":[{"name":"Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343 Cracow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarzyna","family":"Starowicz","sequence":"additional","affiliation":[{"name":"Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343 Cracow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1016\/S0140-6736(05)71086-2","article-title":"Pathogenesis and management of pain in osteoarthritis","volume":"365","author":"Dieppe","year":"2005","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.joca.2011.01.019","article-title":"Osteoarthritis year 2010 in review: Pharmacological therapies","volume":"19","author":"Berenbaum","year":"2011","journal-title":"Osteoarthr. Cart."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.ejpain.2006.02.013","article-title":"Short-term efficacy of pharmacotherapeutic interventions in osteoarthritic knee pain: A meta-analysis of randomised placebo-controlled trials","volume":"11","author":"Bjordal","year":"2007","journal-title":"Eur. J. Pain"},{"key":"ref_4","first-page":"51","article-title":"FAAH and MAGL inhibitors: Therapeutic opportunities from regulating endocannabinoid levels","volume":"11","author":"Petrosino","year":"2010","journal-title":"Curr. Opin. Investig. Drugs"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1946","DOI":"10.1126\/science.1470919","article-title":"Isolation and structure of a brain constituent that binds to the cannabinoid receptor","volume":"258","author":"Devane","year":"1992","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.neuropharm.2006.08.011","article-title":"Changes in spinal and supraspinal endocannabinoid levels in neuropathic rats","volume":"52","author":"Petrosino","year":"2007","journal-title":"Neuropharmacology"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Starowicz, K., Makuch, W., Korostynski, M., Malek, N., Slezak, M., Zychowska, M., Petrosino, S., De Petrocellis, L., Cristino, L., and Przewlocka, B. (2013). Full Inhibition of Spinal FAAH Leads to TRPV1-Mediated Analgesic Effects in Neuropathic Rats and Possible Lipoxygenase-Mediated Remodeling of Anandamide Metabolism. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0060040"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Valastro, C., Campanile, D., Marinaro, M., Franchini, D., Piscitelli, F., Verde, R., Di Marzo, V., and Di Bello, A. (2017). Characterization of endocannabinoids and related acylethanolamides in the synovial fluid of dogs with osteoarthritis: A pilot study. BMC Vet. Res., 13.","DOI":"10.1186\/s12917-017-1245-7"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"R43","DOI":"10.1186\/ar2401","article-title":"Characterisation of the cannabinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis","volume":"10","author":"Richardson","year":"2008","journal-title":"Arthritis Res. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1016\/j.drudis.2010.03.007","article-title":"Endocannabinoid biosynthesis and inactivation, from simple to complex","volume":"15","author":"Muccioli","year":"2010","journal-title":"Drug Discov. Today"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"13345","DOI":"10.1073\/pnas.0601832103","article-title":"A biosynthetic pathway for anandamide","volume":"103","author":"Liu","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neuropharm.2007.05.020","article-title":"Multiple pathways involved in the biosynthesis of anandamide","volume":"54","author":"Liu","year":"2008","journal-title":"Neuropharmacology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1042\/bj20040031","article-title":"Biosynthesis of anandamide and N-palmitoylethanolamine by sequential actions of phospholipase A2 and lysophospholipase D","volume":"380","author":"Sun","year":"2004","journal-title":"Biochem. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1046\/j.1471-4159.2001.00413.x","article-title":"Anandamide degradation and N-acylethanolamines level in wild-type and CB1 cannabinoid receptor knockout mice of different ages","volume":"78","author":"Maccarrone","year":"2001","journal-title":"J. Neurochem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/sj.bjp.0703050","article-title":"The Endogenous Lipid Anandamide is a Full Agonist at the Human Vanilloid Receptor (HVR1)","volume":"129","author":"Smart","year":"2000","journal-title":"Br. J. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3655","DOI":"10.1073\/pnas.97.7.3655","article-title":"Distribution of mRNA for vanilloid receptor subtype 1 (VR1), and VR1-like immunoreactivity, in the central nervous system of the rat and human","volume":"97","author":"Mezey","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1136\/annrheumdis-2013-203413","article-title":"Increased function of pronociceptive TRPV1 at the level of the joint in a rat model of osteoarthritis pain","volume":"74","author":"Kelly","year":"2013","journal-title":"Ann. Rheum. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Braucke, A.F.G.V., Frederiksen, N.L., Berg, L.C., Aarsvold, S., M\u00fcller, F.C., Boesen, M., and Lindegaard, C. (2020). Identification and Quantification of Transient Receptor Potential Vanilloid 1 (TRPV1) in Equine Articular Tissue. Animals, 10.","DOI":"10.3390\/ani10030506"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4433","DOI":"10.3390\/ijms13044433","article-title":"Expression of Transient Receptor Potential Vanilloid (TRPV) Channels in Different Passages of Articular Chondrocytes","volume":"13","author":"Hdud","year":"2012","journal-title":"Int. J. Mol. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1136\/ard.2010.148122","article-title":"The Ile585Val TRPV1 variant is involved in risk of painful knee osteoarthritis","volume":"70","author":"Valdes","year":"2011","journal-title":"Ann. Rheum. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"114","DOI":"10.3390\/ph5020114","article-title":"TRPV1 Antagonists and Chronic Pain: Beyond Thermal Perception","volume":"5","author":"Brandt","year":"2012","journal-title":"Pharmaceuticals"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2687","DOI":"10.2174\/1381612054546789","article-title":"Activation and Activators of TRPV1 and Their Pharmaceutical Implication","volume":"11","author":"Suh","year":"2005","journal-title":"Curr. Pharm. Des."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"7048","DOI":"10.1074\/jbc.M311448200","article-title":"Phosphorylation of Vanilloid Receptor 1 by Ca 2+\/Calmodulin-Dependent Kinase II Regulates Its Vanilloid Binding","volume":"279","author":"Jung","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1097\/j.pain.0000000000000132","article-title":"A multi-target approach for pain treatment","volume":"156","author":"Malek","year":"2015","journal-title":"Pain"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2769","DOI":"10.1038\/s41598-019-39184-4","article-title":"Silencing of spinal Trpv1 attenuates neuropathic pain in rats by inhibiting CAMKII expression and ERK2 phosphorylation","volume":"9","author":"Guo","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0896-6273(02)00908-X","article-title":"p38 MAPK Activation by NGF in Primary Sensory Neurons after Inflammation Increases TRPV1 Levels and Maintains Heat Hyperalgesia","volume":"36","author":"Ji","year":"2002","journal-title":"Neuron"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.coph.2011.10.022","article-title":"Transient receptor potential vanilloid type 1 and pain development","volume":"12","author":"Palazzo","year":"2012","journal-title":"Curr. Opin. Pharm."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"M\u2019Dahoma, S., Bourgoin, S., Kayser, V., Barth\u00e9l\u00e9my, S., Chevarin, C., Chali, F., Orsal, D., and Hamon, M. (2014). Spinal Cord Transection-Induced Allodynia in Rats\u2014Behavioral, Physiopathological and Pharmacological Characterization. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0102027"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.tvjl.2018.11.008","article-title":"Characterization of gene expression in naturally occurring feline degenerative joint disease-associated pain","volume":"243","author":"Ashwell","year":"2019","journal-title":"Vet. J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/s12974-019-1456-x","article-title":"Hyperactivation of proprioceptors induces microglia-mediated long-lasting pain in a rat model of chronic fatigue syndrome","volume":"16","author":"Yasui","year":"2019","journal-title":"J. Neuroinflammation"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4017","DOI":"10.1523\/JNEUROSCI.23-10-04017.2003","article-title":"p38 Mitogen-Activated Protein Kinase Is Activated after a Spinal Nerve Ligation in Spinal Cord Microglia and Dorsal Root Ganglion Neurons and Contributes to the Generation of Neuropathic Pain","volume":"23","author":"Jin","year":"2003","journal-title":"J. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"8300","DOI":"10.1523\/JNEUROSCI.2893-04.2004","article-title":"Phosphatidylinositol 3-Kinase Activates ERK in Primary Sensory Neurons and Mediates Inflammatory Heat Hyperalgesia through TRPV1 Sensitization","volume":"24","author":"Zhuang","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1016\/j.joca.2018.11.006","article-title":"Inhibition of early response genes prevents changes in global joint metabolomic profiles in mouse post-traumatic osteoarthritis","volume":"27","author":"Haudenschild","year":"2019","journal-title":"Osteoarthr. Cartil."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1016\/j.jpain.2018.05.008","article-title":"The Relationship of Endocannabinoidome Lipid Mediators with Pain and Psychological Stress in Women With Fibromyalgia: A Case-Control Study","volume":"19","author":"Stensson","year":"2018","journal-title":"J. Pain"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1097\/01.j.pain.0000460315.80981.59","article-title":"Endocannabinoids and acute pain after total knee arthroplasty","volume":"156","author":"Azim","year":"2015","journal-title":"Pain"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.neuropharm.2013.03.021","article-title":"Anandamide deficiency and heightened neuropathic pain in aged mice","volume":"71","author":"Bishay","year":"2013","journal-title":"Neuropharmacology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3666","DOI":"10.1002\/art.27698","article-title":"Tonic modulation of spinal hyperexcitability by the endocannabinoid receptor system in a rat model of osteoarthritis pain","volume":"62","author":"Sagar","year":"2010","journal-title":"Arthritis Rheum."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1002\/art.23156","article-title":"Cannabinoid-mediated antinociception is enhanced in rat osteoarthritic knees","volume":"58","author":"Schuelert","year":"2007","journal-title":"Arthritis Rheum."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1016\/j.pain.2010.11.025","article-title":"Local application of the endocannabinoid hydrolysis inhibitor URB597 reduces nociception in spontaneous and chemically induced models of osteoarthritis","volume":"152","author":"Schuelert","year":"2011","journal-title":"Pain"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Mlost, J., Kostrzewa, M., Malek, N., and Starowicz, K. (2018). Molecular Understanding of the Activation of CB1 and Blockade of TRPV1 Receptors: Implications for Novel Treatment Strategies in Osteoarthritis. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19020342"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3134","DOI":"10.1111\/bph.13574","article-title":"Robust anti-nociceptive effects of monoacylglycerol lipase inhibition in a model of osteoarthritis pain","volume":"173","author":"Burston","year":"2016","journal-title":"Br. J. Pharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2014\/686908","article-title":"Alterations in the Anandamide Metabolism in the Development of Neuropathic Pain","volume":"2014","author":"Malek","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s13075-017-1229-9","article-title":"Synovitis in osteoarthritis: Current understanding with therapeutic implications","volume":"19","author":"Mathiessen","year":"2017","journal-title":"Arthritis Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/S0163-7258(97)82001-3","article-title":"Pharmacology of cannabinoid CB1 and CB2 receptors","volume":"74","author":"Pertwee","year":"1997","journal-title":"Pharmacol. Ther."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Galindo, T., Reyna, J., and Weyer, A. (2018). Evidence for Transient Receptor Potential (TRP) Channel Contribution to Arthritis Pain and Pathogenesis. Pharm., 11.","DOI":"10.3390\/ph11040105"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Malek, N., and Starowicz, K. (2016). Dual-Acting Compounds Targeting Endocannabinoid and Endovanilloid Systems\u2014A Novel Treatment Option for Chronic Pain Management. Front. Pharmacol., 7.","DOI":"10.3389\/fphar.2016.00257"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1189\/jlb.3RU0115-021R","article-title":"Regulation of inflammation by cannabinoids, the endocannabinoids 2-arachidonoyl-glycerol and arachidonoyl-ethanolamide, and their metabolites","volume":"97","author":"Turcotte","year":"2015","journal-title":"J. Leukoc. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1002\/ejp.818","article-title":"Transdermal cannabidiol reduces inflammation and pain-related behaviours in a rat model of arthritis","volume":"20","author":"Hammell","year":"2015","journal-title":"Eur. J. Pain"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2442","DOI":"10.1097\/j.pain.0000000000001052","article-title":"Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis","volume":"158","author":"Philpott","year":"2017","journal-title":"Pain"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41419-020-02892-1","article-title":"Cannabidiol (CBD): A killer for inflammatory rheumatoid arthritis synovial fibroblasts","volume":"11","author":"Lowin","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Fechtner, S., Singh, A.K., Srivastava, I., Szlenk, C.T., Muench, T.R., Natesan, S., and Ahmed, S. (2019). Cannabinoid Receptor 2 Agonist JWH-015 Inhibits Interleukin-1\u03b2-Induced Inflammation in Rheumatoid Arthritis Synovial Fibroblasts and in Adjuvant Induced Arthritis Rat via Glucocorticoid Receptor. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.01027"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1002\/jbmr.3637","article-title":"Cannabinoid Receptor 2 Agonist Prevents Local and Systemic Inflammatory Bone Destruction in Rheumatoid Arthritis","volume":"34","author":"Zhu","year":"2019","journal-title":"J. Bone Miner. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"109025","DOI":"10.1016\/j.biopha.2019.109025","article-title":"A selective CB2 agonist protects against the inflammatory response and joint destruction in collagen-induced arthritis mice","volume":"116","author":"Bai","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1973","DOI":"10.2147\/JPR.S132682","article-title":"Expression of matrix metalloproteinases and components of the endocannabinoid system in the knee joint are associated with biphasic pain progression in a rat model of osteoarthritis","volume":"10","author":"Pajak","year":"2017","journal-title":"J. Pain Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/19\/7381\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:16:58Z","timestamp":1760177818000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/19\/7381"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,6]]},"references-count":54,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2020,10]]}},"alternative-id":["ijms21197381"],"URL":"https:\/\/doi.org\/10.3390\/ijms21197381","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,6]]}}}