{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:58:15Z","timestamp":1787029095776,"version":"build-2736575974"},"reference-count":65,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2022,7,21]],"date-time":"2022-07-21T00:00:00Z","timestamp":1658361600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Izador I. Cabakoff Research Endowment"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Background: the endocannabinoid system (ECS) participates in many physiological and pathological processes including pain generation, modulation, and sensation. Its involvement in chronic orofacial pain (OFP) in general, and the reflection of its involvement in OFP in salivary endocannabinoid (eCBs) levels in particular, has not been examined. Objectives: to evaluate the association between salivary (eCBs) levels and chronic OFP. Methods: salivary levels of 2 eCBs, anandamide (AEA), 2-arachidonoylglycerol (2-AG), 2 endocannabinoid-like compoundsN-palmitoylethanolamine (PEA), N-oleoylethanolamine (OEA), and their endogenous precursor and breakdown product, arachidonic acid (AA), were analyzed using liquid chromatography\/tandem mass spectrometry in 83 chronic OFP patients and 43 pain-free controls. The chronic OFP patients were divided according to diagnosis into musculoskeletal, neurovascular\/migraine, and neuropathic pain types. Results: chronic OFP patients had lower levels of OEA (p = 0.02) and 2-AG (p = 0.01). Analyzing specific pain types revealed lower levels of AEA and OEA in the neurovascular group (p = 0.04, 0.02, respectively), and 2-AG in the neuropathic group compared to controls (p = 0.05). No significant differences were found between the musculoskeletal pain group and controls. Higher pain intensity was accompanied by lower levels of AA (p = 0.028), in neuropathic group. Conclusions: lower levels of eCBs were found in the saliva of chronic OFP patients compared to controls, specifically those with neurovascular\/migraine, and neuropathic pain. The detection of changes in salivary endocannabinoids levels related to OFP adds a new dimension to our understanding of OFP mechanisms, and may have diagnostic as well as therapeutic implications for pain.<\/jats:p>","DOI":"10.3390\/molecules27144662","type":"journal-article","created":{"date-parts":[[2022,7,21]],"date-time":"2022-07-21T22:38:50Z","timestamp":1658443130000},"page":"4662","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Reduced Endocannabinoid Tone in Saliva of Chronic Orofacial Pain Patients"],"prefix":"10.3390","volume":"27","author":[{"given":"Yaron","family":"Haviv","sequence":"first","affiliation":[{"name":"Department of Oral Medicine, Sedation and Maxillofacial Imaging, Hebrew University-Hadassah School of Dental Medicine, Jerusalem 91120, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Georgiev","sequence":"additional","affiliation":[{"name":"Department of Oral Medicine, Sedation and Maxillofacial Imaging, Hebrew University-Hadassah School of Dental Medicine, Jerusalem 91120, Israel"},{"name":"In Partial Fulfillment of DMD Requirements, Hebrew University-Hadassah School of Dental Medicine, Jerusalem 91120, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tal","family":"Gaver-Bracha","sequence":"additional","affiliation":[{"name":"Department of Oral Medicine, Sedation and Maxillofacial Imaging, Hebrew University-Hadassah School of Dental Medicine, Jerusalem 91120, Israel"},{"name":"In Partial Fulfillment of DMD Requirements, Hebrew University-Hadassah School of Dental Medicine, Jerusalem 91120, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharleen","family":"Hamad","sequence":"additional","affiliation":[{"name":"Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2598-0119","authenticated-orcid":false,"given":"Alina","family":"Nemirovski","sequence":"additional","affiliation":[{"name":"Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rivka","family":"Hadar","sequence":"additional","affiliation":[{"name":"Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yair","family":"Sharav","sequence":"additional","affiliation":[{"name":"Department of Oral Medicine, Sedation and Maxillofacial Imaging, Hebrew University-Hadassah School of Dental Medicine, Jerusalem 91120, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doron J.","family":"Aframian","sequence":"additional","affiliation":[{"name":"Department of Oral Medicine, Sedation and Maxillofacial Imaging, Hebrew University-Hadassah School of Dental Medicine, Jerusalem 91120, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yariv","family":"Brotman","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Ben-Gurion University of the Negev, Beersheba 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0948-0093","authenticated-orcid":false,"given":"Joseph","family":"Tam","sequence":"additional","affiliation":[{"name":"Department of Oral Medicine, Sedation and Maxillofacial Imaging, Hebrew University-Hadassah School of Dental Medicine, Jerusalem 91120, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1038\/npp.2017.204","article-title":"The Endogenous Cannabinoid System: A Budding Source of Targets for Treating Inflammatory and Neuropathic Pain","volume":"43","author":"Donvito","year":"2018","journal-title":"Neuropsychopharmacoly"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1146\/annurev.pharmtox.38.1.179","article-title":"Cannabinoid receptors and their endogenous agonists","volume":"38","author":"Felder","year":"1998","journal-title":"Annu. 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