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We investigated the potential antiallodynic and antihyperalgesic effects of apigenin, a natural flavonoid with momoamine oxidase (MAO) inhibitory activity, against neuropathic pain and investigated the mechanism(s).<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>The neuropathic pain model was produced by chronic constriction injury of sciatic nerves in male C57BL\/6J mice, with pain\u2010related behaviours being assayed by von Frey test and Hargreaves test. In this model the role of 5\u2010HT and 5\u2010HT<jats:sub>1A<\/jats:sub> receptor\u2010related mechanisms were investigated <jats:italic>in vivo<\/jats:italic>\/<jats:italic>in vitro<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Apigenin repeated treatment (p.o., once per day for 2\u2009weeks), in a dose\u2010related manner (3, 10 and 30\u2009mg\u00b7kg<jats:sup>\u22121<\/jats:sup>), ameliorated the allodynia and hyperalgesia in chronic nerve constriction injury in mice. These effects seem dependent on neuronal 5\u2010hydroxytryptamine, because (i) the antihyperalgesia and antiallodynia were attenuated by depletion of 5\u2010HT with <jats:italic>p<\/jats:italic>\u2010chlorophenylalanine and potentiated by 5\u2010hydroxytryptophan and (ii), apigenin\u2010treated chronic constriction injury mice caused an increased level of spinal 5\u2010HT, associated with diminished MAO activity. <jats:italic>In vivo<\/jats:italic> administration, spinally or systematically, of the 5\u2010HT<jats:sub>1A<\/jats:sub> antagonist WAY\u2010100635 inhibited the apigenin\u2010induced antiallodynia and antihyperalgesia. <jats:italic>In vitro<\/jats:italic>, apigenin acted as a positive allosteric modulator to increase the efficacy (stimulation of [<jats:sup>35<\/jats:sup>S]GTP\u03b3S binding) of the 5\u2010HT<jats:sub>1A<\/jats:sub> agonist 8\u2010OH\u2010DPAT. Apigenin attenuated neuronal changes caused by chronic constriction of the sciatic nerve in mice, without causing a hypertensive crisis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Apigenin antiallodynic and antihyperalgesic actions against neuropathic pain crucially involve spinal 5\u2010HT<jats:sub>1A<\/jats:sub> receptors and indicate it could be used to treat neuropathic pain.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15574","type":"journal-article","created":{"date-parts":[[2021,5,24]],"date-time":"2021-05-24T22:25:25Z","timestamp":1621895125000},"page":"4005-4025","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Evidence for 5\u2010HT<sub>1A<\/sub> receptor\u2010mediated antiallodynic and antihyperalgesic effects of apigenin in mice suffering from mononeuropathy"],"prefix":"10.1111","volume":"178","author":[{"given":"Jia\u2010Yi","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Pharmacology Ningbo University, School of Medical Science  Ningbo China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ye","family":"Li","sequence":"additional","affiliation":[{"name":"School of Marine Science Ningbo University  Ningbo China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ben\u2010Ling","family":"Li","sequence":"additional","affiliation":[{"name":"School of Mathematics and Statistics Ningbo University  Ningbo China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan\u2010Gui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Geriatrics Hunan Provincial People's Hospital  Changsha China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wu\u2010Geng","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Ningbo University, School of Medical Science  Ningbo China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen\u2010Hua","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Ningbo University, School of Medical Science  Ningbo China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Ningbo University, School of Medical Science  Ningbo China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,6,22]]},"reference":[{"issue":"1","key":"e_1_2_12_2_1","first-page":"S1","article-title":"The Concise Guide to PHARMACOLOGY 2019\/20: Introduction and other protein targets","volume":"1","author":"Alexander S. 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