Background Persistent neuropathic pain poses a health problem, for which effective therapy or antidote is in dire need. This work aimed to investigate the pain-relieving effect of chrysin, a natural flavonoid with monoamine oxidase inhibitory activity, in an experimental model of neuropathic pain and elucidate mechanism(s).
Methods Chronic constriction injury (CCI) was produced by loose ligation of sciatic nerve in mice. The pain-related behaviors were examined using von Frey test and Hargreaves test. The serotonin-related mechanisms were investigated by serotonin depletion with p-chlorophenylalanine (PCPA) and antagonist tests in vivo and in vitro.
Results Repeated treatment of CCI mice with chrysin (orally, two times per day for 2 weeks) ameliorated heat hyperalgesia and mechanical allodynia in a dose-dependent fashion (3–30 mg/kg). The chrysin-triggered pain relief seems serotonergically dependent, since its antihyperalgesic and antiallodynic actions were abolished by chemical depletion of serotonin by PCPA, whereas potentiated by 5-hydroxytryptophan (a precursor of 5-HT). Consistently, chrysin-treated neuropathic mice showed enhanced levels of spinal monoamines especially 5-HT, with depressed monoamine oxidase activity. Moreover, chrysin-evoked pain relief was preferentially counteracted by 5-HT1A receptor antagonist WAY-100635 delivered systematically or spinally. In vitro, chrysin (0.1–10 nM) increased the maximum effect (Emax, shown as stimulation of [35S] GTPγS binding) of 8-OH-DPAT, a 5-HT1A agonist. Beneficially, chrysin was able to correct comorbid behavioral symptoms of depression and anxiety evoked by neuropathic pain, without causing hypertensive crisis (known as ‘cheese reaction’).
Conclusion These findings confirm the antihyperalgesic and antiallodynic efficacies of chrysin, with spinal 5-HT1A receptors being critically engaged.
- animal experimentation
- chronic pain
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Contributors JW and XZ designed the study. JW, YW and WZ performed the experiments. WC analyzed the data. XZ wrote the manuscript and supervised the whole study.
Funding This project was sponsored by Natural Science Foundation of Zhejiang Province (LY18H310006), Innovative Research Team of Ningbo (2015C110026), K. C. Wong Magna Fund in Ningbo University, Key Research and Development Project of Hunan Provincial Science and Technology Department (2017SK2152) and XinXin Heart (SIP) Foundation (2018-CCA-CMVD-02).
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplementary information. All data relevant to the study are included in the article or uploaded as online supplementary information and data are available on reasonable request.