Upregulation of ERK phosphorylation in rat dorsal root ganglion neurons contributes to oxaliplatin-induced chronic neuropathic pain


Autoři: Toyoaki Maruta aff001;  Takayuki Nemoto aff002;  Koutaro Hidaka aff001;  Tomohiro Koshida aff001;  Tetsuro Shirasaka aff001;  Toshihiko Yanagita aff003;  Ryu Takeya aff004;  Isao Tsuneyoshi aff001
Působiště autorů: Department of Anesthesiology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan aff001;  Department of Pharmacology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan aff002;  Department of Clinical Pharmacology, School of Nursing, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan aff003;  Department of Pharmacology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan aff004
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225586

Souhrn

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.

Klíčová slova:

Allodynia – Apoptosis – Neurons – Neuropathic pain – Neuropathy – Peripheral neuropathy – Phosphorylation – Platinum


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