由于对神经性疼痛的发展和维持的分子机制了解不足,因此治疗神经性疼痛仍然是现代医学的挑战。调节伤害性反应的最重要的级联反应之一是丝裂原活化蛋白(MAP)激酶和磷脂酰肌醇-3-激酶(PI3K)家族,以及核因子红系2相关因子2(Nrf2)。这项研究的目的是确定MAP激酶的非选择性调节剂-非塞素(ERK1/2和NFκB抑制剂,PI3K激活剂),peimine(MAPK抑制剂),虾青素(MAPK抑制剂,Nrf2激活剂)和青蒿素(MAPK抑制剂,NFκB激活剂),以及甲基bardoxolone(Nrf2的选择性激活剂)和740Y-P(PI3K的选择性激活剂)在患有周围神经病变的小鼠中的作用,并比较它们的镇痛效能,并检查它们对阿片类药物诱导的镇痛作用。使用暴露于坐骨神经慢性收缩损伤的白化病瑞士雄性小鼠(CCI模型)进行研究。使用vonFrey和冷板测试测量触觉和热超敏反应,分别。在CCI后第7天鞘内施用单剂量的物质。在测试的物质中,Fisetin,peimine,和虾青素可有效降低CCI后小鼠的触觉和热超敏反应,而青蒿素在这种神经性疼痛模型中没有表现出镇痛效力。此外,测试了两个活化剂,甲基巴多索隆和740Y-P,在暴露于CCI的小鼠鞘内给药后也显示出镇痛作用。在虾青素和甲基巴多索隆的情况下,与吗啡联合给药后镇痛的增加,丁丙诺啡,和/或观察到羟考酮。Fisetin和peimine对触觉超敏反应诱导了类似的效果,给予吗啡或羟考酮后镇痛作用增强。在740Y-P的情况下,仅在热超敏反应的情况下观察到与每种阿片类药物联合给药的效果.我们的研究结果清楚地表明,抑制所有三种MAPK的物质可以缓解疼痛并提高阿片类药物的有效性,特别是如果它们还阻断NF-κB,比如Peimine,抑制NF-κB并激活PI3K,比如Fisetin,或激活Nrf2,如虾青素。根据我们的研究,Nrf2活化似乎是特别有益的。上述物质带来了有希望的结果,对它们的进一步研究将扩大我们对神经病变机制的认识,也许有助于未来更有效的治疗方法的发展。
Treatment of neuropathic pain remains a challenge for modern medicine due to the insufficiently understood molecular mechanisms of its development and maintenance. One of the most important cascades that modulate the nociceptive response is the family of mitogen-activated protein (MAP) kinases and phosphatidylinositol-3-kinase (PI3K), as well as nuclear factor erythroid 2-related factor 2 (Nrf2). The aim of this study was to determine the effect of nonselective modulators of MAP kinases-fisetin (ERK1/2 and NFκB inhibitor, PI3K activator),
peimine (MAPK inhibitor), astaxanthin (MAPK inhibitor, Nrf2 activator) and artemisinin (MAPK inhibitor, NFκB activator), as well as bardoxolone methyl (selective activator of Nrf2) and 740 Y-P (selective activator of PI3K)-in mice with peripheral neuropathy and to compare their antinociceptive potency and examine their effect on analgesia induced by opioids. The study was performed using albino Swiss male mice that were exposed to chronic constriction injury of the sciatic nerve (CCI model). Tactile and thermal hypersensitivity was measured using von Frey and cold plate tests, respectively. Single doses of substances were administered intrathecally on day 7 after CCI. Among the tested substances, fisetin,
peimine, and astaxanthin effectively diminished tactile and thermal hypersensitivity in mice after CCI, while artemisinin did not exhibit analgesic potency in this model of neuropathic pain. Additionally, both of the activators tested, bardoxolone methyl and 740 Y-P, also showed analgesic effects after intrathecal administration in mice exposed to CCI. In the case of astaxanthin and bardoxolone methyl, an increase in analgesia after combined administration with morphine, buprenorphine, and/or oxycodone was observed. Fisetin and
peimine induced a similar effect on tactile hypersensitivity, where analgesia was enhanced after administration of morphine or oxycodone. In the case of 740 Y-P, the effects of combined administration with each opioid were observed only in the case of thermal hypersensitivity. The results of our research clearly indicate that substances that inhibit all three MAPKs provide pain relief and improve opioid effectiveness, especially if they additionally block NF-κB, such as
peimine, inhibit NF-κB and activate PI3K, such as fisetin, or activate Nrf2, such as astaxanthin. In light of our research, Nrf2 activation appears to be particularly beneficial. The abovementioned substances bring promising results, and further research on them will broaden our knowledge regarding the mechanisms of neuropathy and perhaps contribute to the development of more effective therapy in the future.