Metformin antinociceptive effect in models of nociceptive and neuropathic pain is partially mediated by activation of opioidergic mechanisms
Metformin antinociceptive effect in models of nociceptive and neuropathic pain is partially mediated by activation of opioidergic mechanisms
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DOI：
10.1016/j.ejphar.2019.172497
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发表时间：
2019-09-05
影响因子：
5
通讯作者：
Machado, Renes R.
中科院分区：
文献类型：
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作者：
Augusto, Paulo S. A.;Braga, Alysson, V;Machado, Renes R.
二甲双胍是一种AMP激活的蛋白激酶(AMPK)激活剂，是一种口服降糖药，广泛用于治疗2型糖尿病患者。由于AMPK在伤害性反应过程中起作用，因此有必要在疼痛实验模型中研究二甲双胍的作用。在本研究中，我们进一步评估了二甲双胍在伤害性疼痛和神经病理性疼痛模型中的作用，并探讨了可能介导这种作用的机制。二甲双胍单次口服(P.O.)在老鼠身上。采用热(热板)致痛觉反应和慢性缩窄性损伤(CCI)所致的机械性超敏作为疼痛模型。纳曲酮(腹腔注射)和格列本脲(P.O.)用来研究介导二甲双胍效应的机制。在热板模型中，单次给予二甲双胍(500或1000 mg/kg)可抑制伤害性反应。单次和多次给予二甲双胍(250、500、1000 mg/kg)可抑制CCI所致的机械性痛觉异常。二甲双胍(250、500或1000 mg/kg)对小鼠在转杆装置中停留的时间没有影响。纳曲酮(10 mg/kg)可使两种疼痛模型中二甲双胍(1000 mg/kg)的活性减弱，但格列本脲对其无影响。结论是，二甲双胍在伤害性和神经病理性疼痛模型中表现出活性。在神经病理性疼痛模型上，观察其预防和治疗作用。阿片能通路的激活部分介导了二甲双胍的抗伤害性作用。综上所述，这些结果表明，二甲双胍在治疗不同疼痛状况的患者时，应针对其重新定位进行进一步研究。
Metformin, an AMP-activated protein kinase (AMPK) activator, is an oral hypoglycemic drug widely used to treat patients with type 2 diabetes. As AMPK plays a role in the nociceptive processing, investigating the effects induced by metformin in experimental models of pain is warranted. In the present study, we further evaluated the effects induced by metformin in models of nociceptive and neuropathic pain and investigated mechanisms that could mediate such effects. Metformin was administered per os (p.o.) in mice. Nociceptive response induced by heat (hot-plate) and mechanical allodynia induced by chronic constriction injury (CCI) were used as pain models. Naltrexone (intraperitoneal) and glibenclamide (p.o.) were used to investigate mechanisms mediating metformin effects. A single administration of metformin (500 or 1000 mg/kg) inhibited the nociceptive response in the hot-plate model. Single and repeated administration of metformin (250, 500 or 1000 mg/kg) inhibited the mechanical allodynia induced by CCI. Metformin (250, 500 or 1000 mg/kg) did not affect the time mice spent in the rota-rod apparatus. The activity of metformin (1000 mg/kg) in both pain models was attenuated by naltrexone (10 mg/kg), but not by glibenclamide. Concluding, metformin exhibited activity in models of nociceptive and neuropathic pain. In the model of neuropathic pain, preventive and therapeutic effects were observed. Activation of opioidergic pathways partially mediates metformin antinociceptive activity. Altogether, the results indicate that metformin should be further investigated aiming its repositioning in the treatment of patients with different painful conditions.