Upregulation of ERK phosphorylation in rat dorsal root ganglion neurons contributes to oxaliplatin-induced chronic neuropathic pain
Upregulation of ERK phosphorylation in rat dorsal root ganglion neurons contributes to oxaliplatin-induced chronic neuropathic pain
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DOI：
10.1371/journal.pone.0225586
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发表时间：
2019-11-25
期刊：
影响因子：
3.7
通讯作者：
Tsuneyoshi, Isao
中科院分区：
文献类型：
--
作者：
Maruta, Toyoaki;Nemoto, Takayuki;Tsuneyoshi, Isao
奥沙利铂是转移性结直肠癌的一线化疗药物。与其他铂类抗癌药物不同，奥沙利铂不会导致明显的肾功能损害和耳毒性。然而，奥沙利铂与急性和慢性周围神经病有关。尽管认识到这些副作用，但其潜在机制尚未明确。因此，在本研究中，我们旨在了解奥沙利铂治疗引起的慢性神经病变的产生因素。我们建立了奥沙利铂诱导的神经病理性疼痛大鼠模型（腹腔注射4 mg kg(-1)）。在治疗后的不同时间点评估缩爪阈值，与载体治疗相比，奥沙利铂治疗后 3 周和 4 周观察到缩爪阈值显着下降（分别为 4.4 +/- 1.0 与 16.0 +/- 4.1 g；P < 0.05 和 4.4 +/- 0.7 与 14.8 +/- 3.1 g；P < 0.05）。我们进一步评估了不同丝裂原激活蛋白激酶（MAPK）途径在神经性疼痛病理生理学中的作用。尽管奥沙利铂组和媒介物治疗组之间背根神经节 (DRG) 中总细胞外信号调节激酶 (ERK) 1/2 的水平没有差异，但磷酸化 ERK (pERK) 1/2 在奥沙利铂组中上调高达 4.5 倍。 ERK抑制剂PD98059（鞘内注射6μg day(-1)）的给药抑制了奥沙利铂诱导的ERK磷酸化和神经性疼痛。因此，本研究中奥沙利铂对大鼠 DRG 中 p-ERK 的上调以及 ERK 抑制剂对机械异常性疼痛的抑制可能有助于更好地了解与奥沙利铂诱导的神经性疼痛相关的细胞内分子改变，并有助于开发潜在的治疗方法。
Oxaliplatin is the first-line chemotherapy for metastatic colorectal cancer. Unlike other platinum anticancer agents, oxaliplatin does not result in significant renal impairment and ototoxicity. Oxaliplatin, however, has been associated with acute and chronic peripheral neuropathies. Despite the awareness of these side-effects, the underlying mechanisms are yet to be clearly established. Therefore, in this study, we aimed to understand the factors involved in the generation of chronic neuropathy elicited by oxaliplatin treatment. We established a rat model of oxaliplatin-induced neuropathic pain (4 mg kg(-1) intraperitoneally). The paw withdrawal thresholds were assessed at different time-points after the treatment, and a significant decrease was observed 3 and 4 weeks after oxaliplatin treatment as compared to the vehicle treatment (4.4 +/- 1.0 vs. 16.0 +/- 4.1 g; P < 0.05 and 4.4 +/- 0.7 vs. 14.8 +/- 3.1 g; P < 0.05, respectively). We further evaluated the role of different mitogen-activated protein kinases (MAPKs) pathways in the pathophysiology of neuropathic pain. Although the levels of total extracellular signal-regulated kinase (ERK) 1/2 in the dorsal root ganglia (DRG) were not different between oxaliplatin and vehicle treatment groups, phosphorylated ERK (pERK) 1/2 was up-regulated up to 4.5-fold in the oxaliplatin group. Administration of ERK inhibitor PD98059 (6 mu g day(-1) intrathecally) inhibited oxaliplatin-induced ERK phosphorylation and neuropathic pain. Therefore, upregulation of p-ERK by oxaliplatin in rat DRG and inhibition of mechanical allodynia by an ERK inhibitor in the present study may provide a better understanding of intracellular molecular alterations associated with oxaliplatin-induced neuropathic pain and help in the development of potential therapeutics.