Department of Pharmacology, Ningbo University, School of Medical Science, Ningbo, China.
Department of Geriatrics, Hunan Provincial People's Hospital, Changsha, China.
Reg Anesth Pain Med. 2020 Aug;45(8):610-619. doi: 10.1136/rapm-2020-101472. Epub 2020 Jun 18.
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).
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 -chlorophenylalanine (PCPA) and antagonist tests in vivo and in vitro.
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-HT receptor antagonist WAY-100635 delivered systematically or spinally. In vitro, chrysin (0.1-10 nM) increased the maximum effect (Emax, shown as stimulation of [S] GTPγS binding) of 8-OH-DPAT, a 5-HT 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').
These findings confirm the antihyperalgesic and antiallodynic efficacies of chrysin, with spinal 5-HT receptors being critically engaged.
持续性神经病理性疼痛是一个健康问题,迫切需要有效的治疗方法或解毒剂。本工作旨在研究白杨素(一种具有单胺氧化酶抑制活性的天然黄酮类化合物)在神经病理性疼痛实验模型中的镇痛作用,并阐明其机制。
通过坐骨神经的松结扎在小鼠中产生慢性缩窄性损伤(CCI)。使用 von Frey 测试和 Hargreaves 测试检查与疼痛相关的行为。通过体内和体外的 -氯苯丙氨酸(PCPA)和拮抗剂测试研究 5-羟色胺相关机制。
重复给予 CCI 小鼠白杨素(口服,每天两次,共 2 周)以剂量依赖性方式改善热痛觉过敏和机械性痛觉过敏(3-30mg/kg)。白杨素触发的疼痛缓解似乎是 5-羟色胺能依赖的,因为 PCPA 化学耗竭 5-羟色胺后,其抗痛觉过敏和抗痛觉过敏作用被消除,而 5-羟色氨酸(5-HT 的前体)增强。一致地,白杨素治疗的神经病理性小鼠表现出脊髓单胺水平,特别是 5-HT 的增强,同时单胺氧化酶活性降低。此外,全身性或脊髓内给予 5-HT 受体拮抗剂 WAY-100635 优先拮抗白杨素引起的疼痛缓解。在体外,白杨素(0.1-10nM)增加了 5-HT 激动剂 8-OH-DPAT 的最大效应(Emax,表现为[S] GTPγS 结合的刺激)。有益的是,白杨素能够纠正神经病理性疼痛引起的抑郁和焦虑的共病行为症状,而不会引起高血压危象(称为“奶酪反应”)。
这些发现证实了白杨素的抗痛觉过敏和抗痛觉过敏作用,脊髓 5-HT 受体的参与至关重要。