Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, 6627, CEP 31270-901 Belo Horizonte, MG, Brazil.
Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, 6627, CEP 31270-901 Belo Horizonte, MG, Brazil; Centro Universitário Newton Paiva, Avenida Silva Lobo, 1730, CEP 30460-000 Belo Horizonte, MG, Brazil.
Eur J Pharmacol. 2018 Apr 5;824:108-114. doi: 10.1016/j.ejphar.2018.02.014. Epub 2018 Feb 10.
Recently, we demonstrated that nicorandil exhibits activities in models of inflammatory and nociceptive pain. In the present study, we extended this investigation by evaluating the effects of nicorandil in models of neuropathic pain induced by paclitaxel or nerve injury in mice. Four intraperitoneal (i.p.) injections of paclitaxel (2 mg/kg.day, cumulative dose 8 mg/kg) or chronic constriction injury (CCI) of the sciatic nerve induced a long lasting mechanical allodynia. Per os (p.o.) administration of two doses of nicorandil (50, 100 and 150 mg/kg) on the 14th day after the first paclitaxel injection attenuated the mechanical allodynia. Equimolar doses of nicotinamide (86.7 mg/kg, p.o.) or nicotinic acid (87.7 mg/kg, p.o.) were devoid of effect. Mechanical allodynia induced by CCI was also attenuated by p.o. administration of two doses of nicorandil (150 mg/kg) on the 14th day after nerve injury. Nicorandil (50, 100 and 150 mg/kg, p.o.) did not affect motor activity. The antinociceptive activity of nicorandil in the model of mechanical allodynia induced by paclitaxel was partially attenuated by naltrexone (5 and 10 mg/kg, i.p.) or cyproheptadine (5 and 10 mg/kg, i.p.), but not by glibenclamide (20 and 40 mg/kg, p.o.). Concluding, nicorandil exhibits activity in experimental models of neuropathic pain when mechanical allodynia is fully established. Activation of opioidergic and serotonergic pathways mediates the antinociceptive activity of nicorandil. It is unlikely that this activity requires biotransformation to nicotinamide or nicotinic acid. Nicorandil should be further evaluated aiming to identify a new alternative in the pharmacological management of neuropathic pain.
最近，我们证明了尼可地尔在炎症和伤害性疼痛模型中具有活性。在本研究中，我们通过评估尼可地尔在紫杉醇诱导的神经性疼痛模型和小鼠坐骨神经慢性缩窄性损伤模型中的作用，扩展了这一研究。紫杉醇（2mg/kg·天，累积剂量 8mg/kg）腹腔内（i.p.）注射 4 次或坐骨神经慢性缩窄性损伤（CCI）可引起长期的机械性痛觉过敏。在第一次紫杉醇注射后第 14 天，口服给予尼可地尔（50、100 和 150mg/kg）两个剂量可减轻机械性痛觉过敏。等摩尔剂量的烟酰胺（86.7mg/kg，p.o.）或烟酸（87.7mg/kg，p.o.）则没有作用。CCI 引起的机械性痛觉过敏也可通过神经损伤后第 14 天口服给予尼可地尔（150mg/kg）两个剂量来减轻。尼可地尔（50、100 和 150mg/kg，p.o.）不影响运动活动。在紫杉醇诱导的机械性痛觉过敏模型中，尼可地尔的镇痛活性部分被纳洛酮（5 和 10mg/kg，i.p.）或赛庚啶（5 和 10mg/kg，i.p.）减弱，但不受格列本脲（20 和 40mg/kg，p.o.）的影响。结论：当机械性痛觉过敏完全建立时，尼可地尔在实验性神经性疼痛模型中具有活性。阿片能和 5-羟色胺能途径的激活介导了尼可地尔的镇痛作用。这种活性不太可能需要生物转化为烟酰胺或烟酸。尼可地尔应该进一步评估，以确定治疗神经性疼痛的新选择。
