奥沙利铂
神经病理性疼痛
MAPK/ERK通路
医学
背根神经节
痛觉超敏
药理学
下调和上调
激酶
麻醉
磷酸化
内科学
伤害
内分泌学
痛觉过敏
结直肠癌
化学
脊髓
癌症
受体
生物化学
精神科
基因
作者
Toyoaki Maruta,Takayuki Nemoto,Koutaro Hidaka,Tomohiro Koshida,Tetsuro Shirasaka,Toshihiko Yanagita,Ryu Takeya,Isao Tsuneyoshi
出处
期刊:PLOS ONE
[Public Library of Science]
日期:2019-11-25
卷期号:14 (11): e0225586-e0225586
被引量:29
标识
DOI:10.1371/journal.pone.0225586
摘要
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 (p-ERK) 1/2 was up-regulated up to 4.5-fold in the oxaliplatin group. Administration of ERK inhibitor PD98059 (6 μg 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.
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