title: Fisetin exerts antihyperalgesic effect in a mouse model of neuropathic pain: engagement of spinal serotonergic system.
abstract: Fisetin, a natural flavonoid, has been shown in our previous studies to exert antidepressant-like effect. As antidepressant drugs are clinically used to treat chronic neuropathic pain, this work aimed to investigate the potential antinociceptive efficacies of fisetin against neuropathic pain and explore mechanism(s). We subjected mice to chronic constriction injury (CCI) by loosely ligating the sciatic nerves, and Hargreaves test or von Frey test was used to assess thermal hyperalgesia or mechanical allodynia, respectively. Chronic fisetin treatment (5, 15 or 45 mg/kg, p.o.) ameliorated thermal hyperalgesia (but not mechanical allodynia) in CCI mice, concomitant with escalated levels of spinal monoamines and suppressed monoamine oxidase (MAO)-A activity. The antihyperalgesic action of fisetin was abolished by chemical depletion of spinal serotonin (5-HT) but potentiated by co-treatment with 5-HTP, a precursor of 5-HT. Moreover, intraperitoneal (i.p.) or intrathecal (i.t.) co-treatment with 5-HT7 receptor antagonist SB-258719 completely abrogated fisetin's antihyperalgesia. These findings confirm that chronic fisetin treatment exerts antinociceptive effect on thermal hyperalgesia in neuropathic mice, with spinal serotonergic system (coupled with 5-HT7) being critically involved. Of special benefit, fisetin attenuated co-morbidly behavioral symptoms of depression and anxiety (evaluated in forced swim test, novelty suppressed feeding test and light-dark test) evoked by neuropathic pain.
authors.affiliation: Department of Pharmacology, Ningbo University, School of Medical Science, Ningbo, Zhejiang province 315211, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, Ningbo University, School of Medical Science, Ningbo, Zhejiang province 315211, China.
authors.forename: Chuang
authors.initials: C
authors.lastname: Wang
authors.affiliation: Zhejiang Province Key Laboratory of Pathophysiology, Ningbo University, School of Medical Science, Ningbo, Zhejiang province 315211, China.
authors.forename: Wu-Geng
authors.initials: WG
authors.lastname: Cui
authors.affiliation: Department of Pharmacology, Ningbo University, School of Medical Science, Ningbo, Zhejiang province 315211, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Zhejiang Province Key Laboratory of Pathophysiology, Ningbo University, School of Medical Science, Ningbo, Zhejiang province 315211, China.
authors.forename: Wen-Hua
authors.initials: WH
authors.lastname: Zhou
mesh_terms: D006916:5-Hydroxytryptophan / Q000008:administration & dosage / Q000494:pharmacology; D000700:Analgesics / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015306:Biogenic Monoamines / Q000378:metabolism; D004195:Disease Models, Animal; D005419:Flavonoids / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D044948:Flavonols; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008995:Monoamine Oxidase / Q000378:metabolism; D009437:Neuralgia / Q000188:drug therapy / Q000378:metabolism*; D017288:Pain Threshold / Q000187:drug effects; D011985:Receptors, Serotonin; D012701:Serotonin; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D000700:Analgesics; D015306:Biogenic Monoamines; D005419:Flavonoids; D044948:Flavonols; D011985:Receptors, Serotonin; D012701:Serotonin; D006916:5-Hydroxytryptophan; D008995:Monoamine Oxidase; C017875:fisetin