{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T22:56:38Z","timestamp":1778626598268,"version":"3.51.4"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,8,27]],"date-time":"2015-08-27T00:00:00Z","timestamp":1440633600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,8,27]],"date-time":"2015-08-27T00:00:00Z","timestamp":1440633600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Pharmacological blockade of <jats:italic>N<\/jats:italic>-acylethanolamine acid amidase (NAAA) activity is an available approach for inflammation and pain control through restoring the ability of endogenous PEA. But the recently reported NAAA inhibitors suffer from the chemical and biological unstable properties, which restrict functions of NAAA inhibition <jats:italic>in vivo<\/jats:italic>. It is still unrevealed whether systematic inhibition of NAAA could modulate PEA-mediated pain signalings. Here we reported an oxazolidinone imide compound 3-(6-phenylhexanoyl) oxazolidin-2-one (F96), which potently and selectively inhibited NAAA activity (IC<jats:sub>50<\/jats:sub>\u2009=\u2009270\u2009nM). Intraperitoneal (i.p.) injection of F96 (3\u201330\u2009mg\/kg) dose-dependently reduced ear edema and restored PEA levels of ear tissues in 12-<jats:italic>O<\/jats:italic>-Tetradecanoylphorbol-13-acetate (TPA) induced ear edema models. Furthermore, F96 inhibited acetic acid-induced writhing and increased spared nerve injury induced tactile allodynia thresholds in a dose-dependent manner. Pharmacological effects of F96 (10\u2009mg\/kg, i.p.) on various animal models were abolished in PPAR-\u03b1<jats:sup>\u2212\/\u2212<\/jats:sup> mice and were prevented by PPAR-\u03b1 antagonist MK886 but not by canabinoid receptor type 1 (CB<jats:sub>1<\/jats:sub>) antagonist Rimonabant nor canabinoid receptor type 2 (CB<jats:sub>2<\/jats:sub>) antagonist SR144528. Zebrafish embryos experiments showed better security and lower toxicity for F96 than ibuprofen. These results revealed that F96 might be useful in treating inflammatory and neuropathic pain by NAAA inhibition depending on PPAR-\u03b1 receptors.<\/jats:p>","DOI":"10.1038\/srep13565","type":"journal-article","created":{"date-parts":[[2015,8,27]],"date-time":"2015-08-27T09:01:59Z","timestamp":1440666119000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Potential analgesic effects of a novel N-acylethanolamine acid amidase inhibitor F96 through PPAR-\u03b1"],"prefix":"10.1038","volume":"5","author":[{"given":"Longhe","family":"Yang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Long","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanting","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huixia","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuhang","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guangnian","family":"Ji","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donghai","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zuguo","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2015,8,27]]},"reference":[{"key":"BFsrep13565_CR1","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1038\/nn.3612","volume":"17","author":"D Piomelli","year":"2014","unstructured":"Piomelli, D. & Sasso, O. Peripheral gating of pain signals by endogenous lipid mediators. Nat. Neurosci. 17, 164\u2013174 (2014).","journal-title":"Nat. Neurosci."},{"key":"BFsrep13565_CR2","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1111\/ejn.12440","volume":"39","author":"L Luongo","year":"2014","unstructured":"Luongo, L., Maione, S. & Di Marzo, V. Endocannabinoids and neuropathic pain: focus on neuron-glia and endocannabinoid-neurotrophin interactions. Eur. J. Neurosci. 39, 401\u2013408 (2014).","journal-title":"Eur. J. Neurosci."},{"key":"BFsrep13565_CR3","doi-asserted-by":"publisher","first-page":"1051","DOI":"10.1124\/jpet.106.111385","volume":"319","author":"J LoVerme","year":"2006","unstructured":"LoVerme, J. et al. Rapid broad-spectrum analgesia through activation of peroxisome proliferator-activated receptor-alpha. J. Pharmacol. Exp. Ther. 319, 1051\u20131061 (2006).","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"BFsrep13565_CR4","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1124\/mol.104.006353","volume":"67","author":"J Lo Verme","year":"2005","unstructured":"Lo Verme, J. et al. The nuclear receptor peroxisome proliferator-activated receptor-alpha mediates the anti-inflammatory actions of palmitoylethanolamide. Mol. Pharmacol. 67, 15\u201319 (2005).","journal-title":"Mol. Pharmacol."},{"key":"BFsrep13565_CR5","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.pain.2007.03.008","volume":"133","author":"M Suard\u00edaz","year":"2007","unstructured":"Suard\u00edaz, M., Estivill-Torr\u00fas, G., Goicoechea, C., Bilbao, A. & Rodr\u00edguez de Fonseca, F. Analgesic properties of oleoylethanolamide (OEA) in visceral and inflammatory pain. Pain 133, 99\u2013110 (2007).","journal-title":"Pain"},{"key":"BFsrep13565_CR6","doi-asserted-by":"publisher","first-page":"1874","DOI":"10.1111\/febs.12152","volume":"280","author":"N Ueda","year":"2013","unstructured":"Ueda, N., Tsuboi, K. & Uyama, T. Metabolism of endocannabinoids and related N-acylethanolamines: canonical and alternative pathways. FEBS. J. 280, 1874\u20131894 (2013).","journal-title":"FEBS. J."},{"key":"BFsrep13565_CR7","first-page":"99","volume":"26","author":"I Marini","year":"2012","unstructured":"Marini, I., Bartolucci, M. L., Bortolotti, F., Gatto, M. R. & Bonetti, G. A. Palmitoylethanolamide versus a nonsteroidal anti-inflammatory drug in the treatment of temporomandibular joint inflammatory pain. J. Orofac. Pain. 26, 99\u2013104 (2012).","journal-title":"J. Orofac. Pain."},{"key":"BFsrep13565_CR8","first-page":"239","volume":"6","author":"JM Keppel Hesselink","year":"2013","unstructured":"Keppel Hesselink, J. M. & Kopsky, D. J. Treatment of chronic regional pain syndrome type 1 with palmitoylethanolamide and topical ketamine cream: modulation of nonneuronal cells. J. Pain Res. 6, 239\u2013245 (2013).","journal-title":"J. Pain Res."},{"key":"BFsrep13565_CR9","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1111\/j.1526-4637.2010.00823.x","volume":"11","author":"RS Calabr\u00f2","year":"2010","unstructured":"Calabr\u00f2, R. S., Gervasi, G., Marino, S., Mondo, P. N. & Bramanti, P. Misdiagnosed chronic pelvic pain: pudendal neuralgia responding to a novel use of palmitoylethanolamide. Pain Medicine 11, 781\u2013784 (2010).","journal-title":"Pain Medicine"},{"key":"BFsrep13565_CR10","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1016\/j.pain.2012.12.012","volume":"154","author":"BK Taylor","year":"2013","unstructured":"Taylor, B. K. N-acylethanolamine acid amidase (NAAA), a new path to unleash PPAR-mediated analgesia. Pain 154, 326\u2013327 (2013).","journal-title":"Pain"},{"key":"BFsrep13565_CR11","doi-asserted-by":"publisher","first-page":"7","DOI":"10.2174\/1871527311312010005","volume":"12","author":"K Tsuboi","year":"2013","unstructured":"Tsuboi, K. et al. Biosynthetic pathways of bioactive N-acylethanolamines in brain. CNS Neurol. Disord. Drug Targets 12, 7\u201316 (2013).","journal-title":"Disord. Drug Targets"},{"key":"BFsrep13565_CR12","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1016\/j.phrs.2009.11.005","volume":"61","author":"G Endocannabinoid Research","year":"2010","unstructured":"Endocannabinoid Research, G. et al. Levels of endocannabinoids and palmitoylethanolamide and their pharmacological manipulation in chronic granulomatous inflammation in rats. Pharmacol. Res. 61, 321\u2013328 (2010).","journal-title":"Pharmacol. Res."},{"key":"BFsrep13565_CR13","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1016\/j.phrs.2010.02.001","volume":"61","author":"B Costa","year":"2010","unstructured":"Costa, B. et al. The dual fatty acid amide hydrolase\/TRPV1 blocker, N-arachidonoyl-serotonin, relieves carrageenan-induced inflammation and hyperalgesia in mice. Pharmacol. Res. 61, 537\u2013546 (2010).","journal-title":"Pharmacol. Res."},{"key":"BFsrep13565_CR14","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1016\/j.pain.2012.10.018","volume":"154","author":"O Sasso","year":"2013","unstructured":"Sasso, O. et al. Antinociceptive effects of the N-acylethanolamine acid amidase inhibitor ARN077 in rodent pain models. Pain. 154, 350\u2013360 (2013).","journal-title":"Pain."},{"key":"BFsrep13565_CR15","doi-asserted-by":"publisher","first-page":"1914","DOI":"10.1002\/cbdv.200790159","volume":"4","author":"K Tsuboi","year":"2007","unstructured":"Tsuboi, K., Takezaki, N. & Ueda, N. The N-acylethanolamine-hydrolyzing acid amidase (NAAA). Chem Biodivers. 4, 1914\u20131925 (2007).","journal-title":"Chem Biodivers."},{"key":"BFsrep13565_CR16","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/j.plipres.2010.02.003","volume":"49","author":"N Ueda","year":"2010","unstructured":"Ueda, N., Tsuboi, K. & Uyama, T. N-acylethanolamine metabolism with special reference to N-acylethanolamine-hydrolyzing acid amidase (NAAA). Prog. Lipid Res. 49, 299\u2013315 (2010).","journal-title":"Prog. Lipid Res."},{"key":"BFsrep13565_CR17","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.phrs.2014.04.011","volume":"86","author":"T Bandiera","year":"2014","unstructured":"Bandiera, T., Ponzano, S. & Piomelli, D. Advances in the discovery of N-acylethanolamine acid amidase inhibitors. Pharmacol. Res. 86, 11\u201317 (2014).","journal-title":"Pharmacol. Res."},{"key":"BFsrep13565_CR18","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1002\/cmdc.201300416","volume":"9","author":"R Vitale","year":"2014","unstructured":"Vitale, R. et al. Synthesis, structure-activity and structure-stability relationships of 2-substituted-N-(4-oxo-3-oxetanyl) N-acylethanolamine acid amidase (NAAA) inhibitors. ChemMedChem. 9, 323\u2013336 (2014).","journal-title":"ChemMedChem."},{"key":"BFsrep13565_CR19","doi-asserted-by":"publisher","first-page":"10101","DOI":"10.1021\/jm501455s","volume":"57","author":"S Ponzano","year":"2014","unstructured":"Ponzano, S. et al. Synthesis, Biological Evaluation and 3D QSAR Study of 2-Methyl-4-oxo-3-oxetanylcarbamic Acid Esters as N-Acylethanolamine Acid Amidase (NAAA) Inhibitors. J. Med. Chem. 57, 10101\u201310111 (2014).","journal-title":"J. Med. Chem."},{"key":"BFsrep13565_CR20","doi-asserted-by":"publisher","first-page":"1602","DOI":"10.1002\/cmdc.201300546","volume":"9","author":"A Fiasella","year":"2014","unstructured":"Fiasella, A. et al. 3-Aminoazetidin-2-one derivatives as N-acylethanolamine acid amidase (NAAA) inhibitors suitable for systemic administration. ChemMedChem. 9, 1602\u20131614 (2014).","journal-title":"ChemMedChem."},{"key":"BFsrep13565_CR21","doi-asserted-by":"publisher","first-page":"e43023","DOI":"10.1371\/journal.pone.0043023","volume":"7","author":"Y Li","year":"2012","unstructured":"Li, Y. et al. Design and synthesis of potent N-acylethanolamine-hydrolyzing acid amidase (NAAA) inhibitor as anti-inflammatory compounds. PLoS One 7, e43023 (2012).","journal-title":"PLoS One"},{"key":"BFsrep13565_CR22","doi-asserted-by":"publisher","first-page":"4824","DOI":"10.1021\/jm300349j","volume":"55","author":"A Duranti","year":"2012","unstructured":"Duranti, A. et al. N-(2-oxo-3-oxetanyl)carbamic acid esters as N-acylethanolamine acid amidase inhibitors: synthesis and structure-activity and structure-property relationships. J. Med. Chem. 55, 4824\u20134836 (2012).","journal-title":"J. Med. Chem."},{"key":"BFsrep13565_CR23","doi-asserted-by":"publisher","first-page":"20966","DOI":"10.1073\/pnas.0907417106","volume":"106","author":"C Solorzano","year":"2009","unstructured":"Solorzano, C. et al. Selective N-acylethanolamine-hydrolyzing acid amidase inhibition reveals a key role for endogenous palmitoylethanolamide in inflammation. Proc. Natl. Acad. Sci. USA 106, 20966\u201320971 (2009).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFsrep13565_CR24","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1042\/bj20031695","volume":"379","author":"K Tsuboi","year":"2004","unstructured":"Tsuboi, K., Hilligsmann, C., Vandevoorde, S., Lambert, D. M. & Ueda, N. N-cyclohexanecarbonylpentadecylamine: a selective inhibitor of the acid amidase hydrolysing N-acylethanolamines, as a tool to distinguish acid amidase from fatty acid amide hydrolase. Biochem. J. 379, 99\u2013106 (2004).","journal-title":"Biochem. J."},{"key":"BFsrep13565_CR25","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.phrs.2014.10.008","volume":"91","author":"S Petrosino","year":"2015","unstructured":"Petrosino, S. et al. Diacerein is a potent and selective inhibitor of palmitoylethanolamide inactivation with analgesic activity in a rat model of acute inflammatory pain. Pharmacol. Res. 91, 9\u201314 (2015).","journal-title":"Pharmacol. Res."},{"key":"BFsrep13565_CR26","doi-asserted-by":"crossref","unstructured":"Ribeiro, A. et al. A Potent Systemically Active N-Acylethanolamine Acid Amidase Inhibitor that Suppresses Inflammation and Human Macrophage Activation. ACS Chem. Biol. (2015).","DOI":"10.1021\/acschembio.5b00114"},{"key":"BFsrep13565_CR27","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1096\/fj.14-255208","volume":"29","author":"M Alhouayek","year":"2015","unstructured":"Alhouayek, M. et al. N-Acylethanolamine-hydrolyzing acid amidase inhibition increases colon N-palmitoylethanolamine levels and counteracts murine colitis. FASEB. J. 29, 650\u2013661 (2015).","journal-title":"FASEB. J."},{"key":"BFsrep13565_CR28","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1038\/bjp.2008.324","volume":"155","author":"WS Ho","year":"2008","unstructured":"Ho, W. S., Barrett, D. A. & Randall, M. D. \u2018Entourage\u2019 effects of N-palmitoylethanolamide and N-oleoylethanolamide on vasorelaxation to anandamide occur through TRPV1 receptors. Br. J. Pharmacol. 155, 837\u2013846 (2008).","journal-title":"Br. J. Pharmacol."},{"key":"BFsrep13565_CR29","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/j.beem.2008.09.003","volume":"23","author":"FA Moreira","year":"2009","unstructured":"Moreira, F. A., Grieb, M. & Lutz, B. Central side-effects of therapies based on CB 1 cannabinoid receptor agonists and antagonists: focus on anxiety and depression. Best Pract. Res. Clin. Endocrinol. Metab. 23, 133\u2013144 (2009).","journal-title":"Best Pract. Res. Clin. Endocrinol. Metab."},{"key":"BFsrep13565_CR30","doi-asserted-by":"publisher","first-page":"20270","DOI":"10.1073\/pnas.0909411106","volume":"106","author":"JZ Long","year":"2009","unstructured":"Long, J. Z. et al. Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo. Proc. Natl. Acad. Sci. USA 106, 20270\u201320275 (2009).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFsrep13565_CR31","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.1038\/nn.2632","volume":"13","author":"JR Clapper","year":"2010","unstructured":"Clapper, J. R. et al. Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism. Nat. Neurosci. 13, 1265\u20131270 (2010).","journal-title":"Nat. Neurosci."},{"key":"BFsrep13565_CR32","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/S0014-2999(98)00392-6","volume":"353","author":"S Ben-Shabat","year":"1998","unstructured":"Ben-Shabat, S. et al. An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur. J. Pharmacol. 353, 23\u201331 (1998).","journal-title":"Eur. J. Pharmacol."},{"key":"BFsrep13565_CR33","doi-asserted-by":"publisher","first-page":"5899","DOI":"10.1021\/cr2002799","volume":"111","author":"CA Rouzer","year":"2011","unstructured":"Rouzer, C. A. & Marnett, L. J. Endocannabinoid oxygenation by cyclooxygenases, lipoxygenases and cytochromes P450: cross-talk between the eicosanoid and endocannabinoid signaling pathways. Chem. Rev. 111, 5899\u20135921 (2011).","journal-title":"Chem. Rev."},{"key":"BFsrep13565_CR34","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1016\/j.celrep.2012.05.001","volume":"1","author":"JR Piro","year":"2012","unstructured":"Piro, J. R. et al. A dysregulated endocannabinoid-eicosanoid network supports pathogenesis in a mouse model of Alzheimer\u2019s disease. Cell reports 1, 617\u2013623 (2012).","journal-title":"Cell reports"},{"key":"BFsrep13565_CR35","doi-asserted-by":"publisher","first-page":"842","DOI":"10.1111\/j.1471-4159.2011.07625.x","volume":"120","author":"X Wu","year":"2012","unstructured":"Wu, X. et al. Alteration of endocannabinoid system in human gliomas. J. Neurochem. 120, 842\u2013849 (2012).","journal-title":"J. Neurochem."},{"key":"BFsrep13565_CR36","doi-asserted-by":"publisher","first-page":"13637","DOI":"10.3390\/ijms150813637","volume":"15","author":"L Yang","year":"2014","unstructured":"Yang, L. et al. Celastrol attenuates inflammatory and neuropathic pain mediated by cannabinoid receptor type 2. Int. J. Mol. Sci. 15, 13637\u201313648 (2014).","journal-title":"Int. J. Mol. Sci."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep13565","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep13565.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep13565.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T22:54:38Z","timestamp":1672959278000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep13565"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,8,27]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,10,16]]}},"alternative-id":["BFsrep13565"],"URL":"https:\/\/doi.org\/10.1038\/srep13565","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,8,27]]},"assertion":[{"value":"18 March 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 July 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 August 2015","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"13565"}}