Department of Pain Pharmacology, Maj Institute of Pharmacology Polish Academy of Sciences, 12 Smetna Str., 31-343 Krakow, Poland.
Int J Mol Sci. 2023 May 19;24(10):9000. doi: 10.3390/ijms24109000.
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.
治疗神经性疼痛仍然是现代医学的一个挑战，因为其发展和维持的分子机制尚未得到充分理解。调节伤害性反应最重要的级联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，以及核因子红细胞 2 相关因子 2（Nrf2）。本研究的目的是确定非选择性 MAP 激酶调节剂的效果 - 非瑟酮（ERK1/2 和 NFκB 抑制剂，PI3K 激活剂）、佩米酮（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 bardoxolone 甲基（Nrf2 的选择性激活剂）和 740 Y-P（PI3K 的选择性激活剂）对周围神经病变的小鼠的影响，并比较它们的镇痛效力，并研究它们对阿片类药物诱导的镇痛作用的影响。本研究使用暴露于坐骨神经慢性缩窄性损伤（CCI 模型）的白化瑞士雄性小鼠进行。使用 von Frey 和冷板测试分别测量触觉和热敏性。在 CCI 后第 7 天，通过鞘内给予单剂量物质。在测试的物质中，非瑟酮、佩米酮和虾青素可有效减轻 CCI 后小鼠的触觉和热敏性，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，在鞘内给予 CCI 暴露的小鼠后，两种测试的激活剂，bardoxolone 甲基和 740 Y-P，也表现出镇痛作用。在虾青素和 bardoxolone 甲基的情况下，观察到与吗啡、丁丙诺啡和/或羟考酮联合给药后镇痛作用增加。非瑟酮和佩米酮对触觉过敏产生类似的影响，其中给予吗啡或羟考酮后镇痛作用增强。在 740 Y-P 的情况下，仅在热敏性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 的物质可缓解疼痛并提高阿片类药物的疗效，特别是如果它们还阻断 NF-κB，如佩米酮，抑制 NF-κB 并激活 PI3K，如非瑟酮，或激活 Nrf2，如虾青素。根据我们的研究，Nrf2 激活似乎特别有益。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机制的认识，并有助于未来开发更有效的治疗方法。
