Vieira Graziela, Cavalli Juliana, Gonçalves Elaine C D, Gonçalves Tainara R, Laurindo Larissa R, Cola Maíra, Dutra Rafael C
Laboratory of Autoimmunity and Immunopharmacology (LAIF), Department of Health Sciences, Center of Araranguá, Federal University of Santa CatarinaAraranguá, Brazil.
Post-Graduate Program of Cellular Biology and Developmental, Center of Biological Sciences, Federal University of Santa CatarinaFlorianópolis, Brazil.
Front Pharmacol. 2017 Sep 4;8:584. doi: 10.3389/fphar.2017.00584. eCollection 2017.
Simvastatin is a lipid-lowering agent that blocks the production of cholesterol through inhibition of 3-hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase. In addition, recent evidence has suggested its anti-inflammatory and antinociceptive actions during inflammatory and pain disorders. Herein, we investigated the effects of simvastatin in an animal model of complex regional pain syndrome-type I, and its underlying mechanisms. Chronic post-ischemia pain (CPIP) was induced by ischemia and reperfusion (IR) injury of the left hind paw. Our findings showed that simvastatin inhibited mechanical hyperalgesia induced by CPIP model in single and repeated treatment schedules, respectively; however simvastatin did not alter inflammatory signs during CPIP model. The mechanisms underlying those actions are related to modulation of transient receptor potential (TRP) channels, especially TRMP8. Moreover, simvastatin oral treatment was able to reduce the nociception induced by acidified saline [an acid-sensing ion channels (ASICs) activator] and bradykinin (BK) stimulus, but not by TRPA1, TRPV1 or prostaglandin-E2 (PGE2). Relevantly, the antinociceptive effects of simvastatin did not seem to be associated with modulation of the descending pain circuits, especially noradrenergic, serotoninergic and dopaminergic systems. These results indicate that simvastatin consistently inhibits mechanical hyperalgesia during neuropathic and inflammatory disorders, possibly by modulating the ascending pain signaling (TRPM8/ASIC/BK pathways expressed in the primary sensory neuron). Thus, simvastatin open-up new standpoint in the development of innovative analgesic drugs for treatment of persistent pain, including CRPS-I.
辛伐他汀是一种降脂药物，通过抑制3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶来阻止胆固醇的生成。此外，最近有证据表明其在炎症和疼痛性疾病中具有抗炎和抗伤害感受作用。在此，我们研究了辛伐他汀在I型复杂性区域疼痛综合征动物模型中的作用及其潜在机制。通过左后爪的缺血再灌注（IR）损伤诱导慢性缺血后疼痛（CPIP）。我们的研究结果表明，辛伐他汀在单次和重复治疗方案中均能抑制CPIP模型诱导的机械性痛觉过敏；然而，辛伐他汀在CPIP模型中并未改变炎症体征。这些作用的潜在机制与瞬时受体电位（TRP）通道的调节有关，尤其是TRPM8。此外，辛伐他汀口服治疗能够减轻由酸化盐水[一种酸敏感离子通道（ASICs）激活剂]和缓激肽（BK）刺激诱导的伤害感受，但对TRPA1、TRPV1或前列腺素E2（PGE2）诱导的伤害感受无效。相关地，辛伐他汀的抗伤害感受作用似乎与下行疼痛回路的调节无关，尤其是去甲肾上腺素能、5-羟色胺能和多巴胺能系统。这些结果表明，辛伐他汀在神经性和炎症性疾病中持续抑制机械性痛觉过敏，可能是通过调节上行疼痛信号传导（初级感觉神经元中表达的TRPM8/ASIC/BK途径）。因此，辛伐他汀为开发用于治疗持续性疼痛（包括CRPS-I）的创新镇痛药开辟了新的视角。
