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The mechanisms underlying the upregulation are not fully understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aims<\/jats:title><jats:p>The present study aims to investigate the regulatory effect of histamine on the expression of Nav1.8 in primary afferent neurons and its involvement in neuropathic pain.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Histamine at 10<jats:sup>\u22128<\/jats:sup>\u00a0M increased the expression of Nav1.8 in cultured <jats:styled-content style=\"fixed-case\">DRG<\/jats:styled-content> neurons. This effect could be blocked by H<jats:sub>2<\/jats:sub> receptor antagonist cimetidine or famotidine, but not by H<jats:sub>1<\/jats:sub> receptor antagonist pyrilamine or dual H<jats:sub>3<\/jats:sub>\/H<jats:sub>4<\/jats:sub> antagonist thioperamide. Peri\u2010sciatic administration of histamine increased Nav1.8 expression in the sciatic nerve and L4\/L5 <jats:styled-content style=\"fixed-case\">DRG<\/jats:styled-content> neurons in a dose\u2010dependent manner, accompanied with remarkable mechanical allodynia and heat hyperalgesia in the ipsilateral hindpaw. Famotidine but not pyrilamine or thioperamide inhibited Nav1.8 upregulation and pain hypersensitivity. In addition, famotidine (40\u00a0mg\/kg, i.p.) not only suppressed autotomy behavior in the rat neuroma model of neuropathic pain but also attenuated mechanical allodynia and thermal hyperalgesia following partial sciatic nerve ligation. Moreover, famotidine inhibited Nav1.8 upregulation in the neuroma and ligated sciatic nerve.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings indicate that histamine increases Nav1.8 expression in primary afferent neurons via H<jats:sub>2<\/jats:sub> receptor\u2010mediated pathway and thereby contributes to neuropathic pain. H<jats:sub>2<\/jats:sub> receptor antagonists may potentially be used as analgesics for patients with neuropathic pain.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.12305","type":"journal-article","created":{"date-parts":[[2014,7,3]],"date-time":"2014-07-03T08:36:09Z","timestamp":1404376569000},"page":"883-892","source":"Crossref","is-referenced-by-count":25,"title":["Histamine Upregulates Nav1.8 Expression in Primary Afferent Neurons via H<sub>2<\/sub> Receptors: Involvement in Neuropathic Pain"],"prefix":"10.1111","volume":"20","author":[{"given":"Jia\u2010Xing","family":"Yue","sequence":"first","affiliation":[{"name":"Department of Pharmacology Key Laboratory of Medical Neurobiology of the Ministry of Health of China School of Basic Medicine Zhejiang University Hangzhou China"},{"name":"Department of Pharmacology College of Pharmaceutical Sciences Zhejiang University Hangzhou 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