Rojewska Ewelina, Popiolek-Barczyk Katarzyna, Kolosowska Natalia, Piotrowska Anna, Zychowska Magdalena, Makuch Wioletta, Przewlocka Barbara, Mika Joanna
Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
PLoS One. 2015 Oct 1;10(10):e0138583. doi: 10.1371/journal.pone.0138583. eCollection 2015.
Neuropathic pain treatment remains challenging due to ineffective therapy and resistance to opioid analgesia. Mitogen-activated protein kinase kinase (MAPKK) have been identified as the crucial regulators of pro- and antinociceptive factors. We used PD98059, an inhibitor of the MAPKK family members MEK1/2. The aim of study was to examine the influence of single and/or repeated PD98059 on nociception and opioid effectiveness in neuropathy. Moreover, we examined how PD98059 influences selected members of cellular pathways and cytokines. The PD98059 (2.5 mcg) was intrathecally preemptively administered before chronic constriction injury (CCI), and then once daily for 7 days. Additionally, at day 7 after CCI the PD98059-treated rats received a single injection of opioids. Using Western blot and qRT-PCR techniques in PD98059-treated rats we analyzed the mRNA and/or protein level of p38, ERK1/2, JNK, NF-kappaB, IL-1beta, IL-6, iNOS and IL-10 in the lumbar spinal cord. Our results indicate that PD98059 has an analgesic effects and potentiates morphine and/or buprenorphine analgesia. Parallel we observed that PD98059 inhibit upregulation of the CCI-elevated p38, ERK1/2, JNK and NF-kappaB protein levels. Moreover, PD98059 also prevented increase of pro- (IL-1beta, IL-6, and iNOS) but enhances anti-nociceptive (IL-10) factors. Summing up, PD98059 diminished pain and increased the effectiveness of opioids in neuropathy. The inhibition of MEKs might inactivate a variety of cell signaling pathways that are implicated in nociception.
由于治疗效果不佳以及对阿片类镇痛药物产生耐药性，神经性疼痛的治疗仍然具有挑战性。丝裂原活化蛋白激酶激酶（MAPKK）已被确定为促伤害性感受因子和抗伤害性感受因子的关键调节因子。我们使用了PD98059，一种MAPKK家族成员MEK1/2的抑制剂。本研究的目的是研究单次和/或重复使用PD98059对神经病变中伤害感受和阿片类药物有效性的影响。此外，我们还研究了PD98059如何影响细胞通路和细胞因子的选定成员。在慢性缩窄损伤（CCI）之前，鞘内预先给予PD98059（2.5微克），然后每天一次，持续7天。此外，在CCI后第7天，接受PD98059治疗的大鼠接受单次阿片类药物注射。我们使用蛋白质免疫印迹法和qRT-PCR技术，分析了PD98059治疗大鼠腰段脊髓中p38、ERK1/2、JNK、NF-κB、IL-1β、IL-6、诱导型一氧化氮合酶（iNOS）和IL-10的mRNA和/或蛋白质水平。我们的结果表明，PD98059具有镇痛作用，并增强吗啡和/或丁丙诺啡的镇痛效果。与此同时，我们观察到PD98059可抑制CCI引起的p38、ERK1/2、JNK和NF-κB蛋白水平的上调。此外，PD98059还可防止促炎因子（IL-1β、IL-6和iNOS）的增加，但增强抗伤害性感受因子（IL-10）。总之，PD98059可减轻神经病变中的疼痛并提高阿片类药物的有效性。抑制MEK可能会使多种与伤害感受相关的细胞信号通路失活。
