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Here, we investigated the ability of \u0394\n 9<\/jats:sup>\n \u2010THCA\u2010A to modulate the classic cannabinoid CB\n 1<\/jats:sub>\n and CB\n 2<\/jats:sub>\n receptors and evaluated its anti\u2010arthritis activity in vitro and in vivo.\n <\/jats:p>\n <\/jats:sec>\n \n Experimental Approach<\/jats:title>\n \n Cannabinoid receptors binding and intrinsic activity, as well as their downstream signalling, were analysed in vitro and in silico. The anti\u2010arthritis properties of \u0394\n 9<\/jats:sup>\n \u2010THCA\u2010A were studied in human chondrocytes and in the murine model of collagen\u2010induced arthritis (CIA). Plasma disease biomarkers were identified by LC\u2010MS\/MS based on proteomic and\n elisa<\/jats:sc>\n assays.\n <\/jats:p>\n <\/jats:sec>\n \n Key Results<\/jats:title>\n \n Functional and docking analyses showed that \u0394\n 9<\/jats:sup>\n \u2010THCA\u2010A can act as an orthosteric CB\n 1<\/jats:sub>\n receptor agonist and also as a positive allosteric modulator in the presence of CP\u201055,940. Also, \u0394\n 9<\/jats:sup>\n \u2010THCA\u2010A seemed to be an inverse agonist for CB\n 2<\/jats:sub>\n receptors. In vivo, \u0394\n 9<\/jats:sup>\n \u2010THCA\u2010A reduced arthritis in CIA mice, preventing the infiltration of inflammatory cells, synovium hyperplasia, and cartilage damage. Furthermore, \u0394\n 9<\/jats:sup>\n \u2010THCA\u2010A inhibited expression of inflammatory and catabolic genes on knee joints. The anti\u2010arthritic effect of \u0394\n 9<\/jats:sup>\n \u2010THCA\u2010A was blocked by either SR141716 or T0070907. Analysis of plasma biomarkers, and determination of cytokines and anti\u2010collagen antibodies confirmed that \u0394\n 9<\/jats:sup>\n \u2010THCA\u2010A mediated its activity mainly through PPAR\u03b3 and CB\n 1<\/jats:sub>\n receptor pathways.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion and Implications<\/jats:title>\n \n \u0394\n 9<\/jats:sup>\n \u2010THCA\u2010A modulates CB\n 1<\/jats:sub>\n receptors through the orthosteric and allosteric binding sites. In addition, \u0394\n 9<\/jats:sup>\n \u2010THCA\u2010A exerts anti\u2010arthritis activity through CB\n 1<\/jats:sub>\n receptors and PPAR\u03b3 pathways, highlighting its potential for the treatment of chronic inflammatory diseases such as rheumatoid arthritis.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/bph.15155","type":"journal-article","created":{"date-parts":[[2020,6,8]],"date-time":"2020-06-08T08:31:09Z","timestamp":1591605069000},"page":"4034-4054","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["\u0394\n 9<\/sup>\n \u2010Tetrahydrocannabinolic acid alleviates collagen\u2010induced arthritis: Role of PPAR\u03b3 and CB\n 1<\/sub>\n receptors"],"prefix":"10.1111","volume":"177","author":[{"given":"Bel\u00e9n","family":"Palomares","sequence":"first","affiliation":[{"name":"Maimonides Biomedical Research Institute of C\u00f3rdoba University of C\u00f3rdoba C\u00f3rdoba Spain"},{"name":"Department of Cellular 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