Li Nannan, Li Chunmei, Han Rui, Wang Yu, Yang Mina, Wang Hongbo, Tian Jingwei
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China.
Front Pharmacol. 2019 Feb 14;10:53. doi: 10.3389/fphar.2019.00053. eCollection 2019.
Sedation and somnolence remain serious adverse effects of the existing analgesics (e.g., pregabalin, duloxetine) for neuropathic pain. The available evidence indicates that serotonin (5-HT), noradrenaline (NE), and dopamine (DA) play important roles in modulating the descending inhibitory pain pathway and sleep-wake cycle. The aim of this work was to test the hypothesis that LPM580098, a novel triple reuptake inhibitor (TRI) of 5-HT, NE, and DA, has analgesic effect, and does not induce significant adverse effects associated with central inhibition, such as sedation and somnolence. The analgesic activity of LPM580098 was assessed on formalin test and spinal nerve ligation (SNL)-induced neuropathic pain model. Locomotor activity, pentobarbital sodium-induced sleeping and rota-rod tests were also conducted. binding and uptake assays, and Western blotting were performed to examine the potential mechanisms. LPM580098 suppressed the nocifensive behaviors during phase II of the formalin test in mice. In SNL rats, LPM580098 (16 mg kg) inhibited mechanical allodynia, thermal hyperalgesia and hyperexcitation of wide-dynamic range (WDR) neurons, in which the effect of LPM580098 was similar to pregabalin (30 mg kg). However, pregabalin altered the spontaneous locomotion, affected pentobarbital sodium-induced sleep, and showed a trend to perform motor dysfunction, which were not induced by LPM580098. Mechanistically, LPM580098 inhibited the uptake of 5-HT, NE, and DA, improved pain-induced changes of the synaptic functional plasticity and structural plasticity possibly via downregulating the NR2B/CaMKIIα/GluR1 and Rac1/RhoA signaling pathways. Our results suggest that LPM580098, a novel TRI, is effective in attenuating neuropathic pain without producing unwanted sedation and somnolence associated with central nervous system (CNS) depressants.
镇静和嗜睡仍然是现有用于治疗神经性疼痛的镇痛药（如普瑞巴林、度洛西汀）的严重不良反应。现有证据表明，5-羟色胺（5-HT）、去甲肾上腺素（NE）和多巴胺（DA）在调节下行抑制性疼痛通路和睡眠-觉醒周期中发挥重要作用。本研究的目的是验证一种新型的5-HT、NE和DA三重再摄取抑制剂（TRI）LPM580098具有镇痛作用，且不会引起与中枢抑制相关的显著不良反应（如镇静和嗜睡）这一假设。通过福尔马林试验和脊髓神经结扎（SNL）诱导的神经性疼痛模型评估了LPM580098的镇痛活性。还进行了自主活动、戊巴比妥钠诱导睡眠和转棒试验。进行了结合和摄取试验以及蛋白质印迹分析以研究潜在机制。LPM580098抑制了小鼠福尔马林试验第二阶段的伤害性反应行为。在SNL大鼠中，LPM580098（16mg/kg）抑制了机械性异常性疼痛、热痛觉过敏以及广动力范围（WDR）神经元的过度兴奋，其中LPM580098的作用与普瑞巴林（30mg/kg）相似。然而，普瑞巴林改变了自发运动，影响了戊巴比妥钠诱导的睡眠，并表现出运动功能障碍的趋势，而LPM580098未诱导这些情况。从机制上讲，LPM580098抑制了5-HT、NE和DA的摄取，可能通过下调NR2B/CaMKIIα/GluR1和Rac1/RhoA信号通路改善了疼痛诱导的突触功能可塑性和结构可塑性变化。我们的结果表明，新型TRI LPM580098在减轻神经性疼痛方面有效，且不会产生与中枢神经系统（CNS）抑制剂相关的不良镇静和嗜睡作用。
