Psychobiology Group/Department of Psychology/CECH-UFSCar, São Carlos, SP 13565-905, Brazil; Joint Graduate Program in Physiological Sciences UFSCar/UNESP., São Carlos, SP 13565-905, Brazil; Department of Neuroscience, Psychology, Drug Research and Child Health - Neurofarba - Pharmacology and Toxicology Section, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
Department of Neuroscience, Psychology, Drug Research and Child Health - Neurofarba - Pharmacology and Toxicology Section, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
Eur J Pharmacol. 2014 Jul 15;735:141-9. doi: 10.1016/j.ejphar.2014.04.028. Epub 2014 Apr 29.
Fluoxetine has been shown to be effective in clinical and experimental studies of neuropathic pain. Besides to increase serotonin levels in the synaptic cleft, fluoxetine is able to block the serotonergic 5-HT2C receptor subtype, which in turn has been involved in the modulation of neuropathic pain. This study investigated the effect of repeated treatments with fluoxetine on the neuropathic nociceptive response induced by oxaliplatin and the effects of both treatments on 5-HT2C receptor mRNA expression and protein levels in the rat spinal cord (SC), rostral ventral medulla (RVM), midbrain periaqueductal gray (PAG) and amygdala (Amy). Nociception was assessed by paw-pressure, cold plate and Von Frey tests. Fluoxetine prevented mechanical hypersensitivity and pain threshold alterations induced by oxaliplatin but did not prevent the impairment in weight gain induced by this anticancer drug. Ex vivo analysis revealed that oxaliplatin increased the 5-HT2C receptor mRNA expression and protein levels in the SC and PAG. Similar effects were observed in fluoxetine-treated animals but only within the PAG. While oxaliplatin decreased the 5-HT2C mRNA expression levels in the Amy, fluoxetine increased their protein levels in this area. Fluoxetine impaired the oxaliplatin effects on the 5-HT2C receptor mRNA expression in the SC and Amy and protein levels in the SC. All treatments increased of 5-HT2C receptor mRNA expression and protein levels in the PAG. These results suggest that the effects of fluoxetine on neuropathic pain induced by oxaliplatin are associated with quantitative changes in the 5-HT2C receptors located within important areas of the nociceptive system.
氟西汀已被证明在神经病理性疼痛的临床和实验研究中有效。除了增加突触间隙中的 5-羟色胺水平外，氟西汀还能够阻断 5-羟色胺能 5-HT2C 受体亚型，该受体亚型参与了神经病理性疼痛的调制。本研究调查了重复使用氟西汀对奥沙利铂诱导的神经病理性伤害性反应的影响，以及这两种治疗方法对大鼠脊髓 (SC)、延髓头端腹内侧 (RVM)、中脑导水管周围灰质 (PAG) 和杏仁核 (Amy) 中 5-HT2C 受体 mRNA 表达和蛋白水平的影响。伤害性感受通过足底压力、冷板和 Von Frey 试验进行评估。氟西汀可预防奥沙利铂引起的机械性过敏和痛阈改变，但不能预防这种抗癌药物引起的体重减轻。体外分析显示，奥沙利铂增加了 SC 和 PAG 中的 5-HT2C 受体 mRNA 表达和蛋白水平。在接受氟西汀治疗的动物中也观察到了类似的效应，但仅在 PAG 中观察到。虽然奥沙利铂降低了 Amy 中 5-HT2C mRNA 的表达水平，但氟西汀增加了该区域的蛋白水平。氟西汀损害了奥沙利铂对 SC 和 Amy 中 5-HT2C 受体 mRNA 表达和 SC 中蛋白水平的影响。所有治疗均增加了 PAG 中 5-HT2C 受体 mRNA 表达和蛋白水平。这些结果表明，氟西汀对奥沙利铂引起的神经病理性疼痛的影响与位于疼痛系统重要区域的 5-HT2C 受体的定量变化有关。
