Fisetin exerts antihyperalgesic effect in a mouse model of neuropathic pain: engagement of spinal serotonergic system.

Xin Zhao,Chuang Wang,Qing Ma,Wen-Hua Zhou,Wu-Geng Cui

doi:10.1038/srep09043

Xin Zhao, Chuang Wang + Show 3 more

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https://doi.org/10.1038/srep09043

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Journal: Scientific Reports	Publication Date: Mar 12, 2015
Citations: 31	License type: CC BY 4.0

Affiliation: Ningbo University

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.

Highlights

Fisetin exerts antihyperalgesic effect in a mouse model of neuropathic pain: engagement of spinal serotonergic system
After 3 weeks treatment, fisetin markedly attenuated in constriction injury (CCI) mice the pronounced thermal hyperalgesia (F7,284 5 12.6, p, 0.01; Fig. 2A) in a dose-dependent manner, with significant difference at doses of 15 mg/kg and 45 mg/kg
The antihyperalgesia by fisetin may depend on the activation of descending serotonergic system, which is coupled with spinal 5-HT7 receptors

Summary

Introduction

Fisetin exerts antihyperalgesic effect in a mouse model of neuropathic pain: engagement of spinal serotonergic system. 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). 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. N europathic pain is usually an enduring and devastating condition resulting from damage to nociceptive pathways in the peripheral or central nervous system[1] This disease represents a significant challenge in clinical practice due to, at least partly, its multi-facet etiologies, symptoms and underlying mechanisms[2]. Co-treatment with 5-HTP PCPA 6-OHDA 5-HT Antagonists evaluated whether fisetin engenders beneficial effects on the co-morbidly behavioral phenotypes of depression and anxiety evoked by chronic neuropathic pain

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