Title:Oxaliplatin Regulates Chemotherapy Induced Peripheral Neuropathic Pain in the Dorsal Horn and Dorsal Root Ganglion via the Calcineurin/NFAT Pathway
VOLUME: 18 ISSUE: 8
Author(s):Wan Huang*, Jingxiu Huang, Yu Jiang, Xuanwei Huang, Wei Xing, Yaoxuan He and Handong Ouyang
Affiliation:Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China，Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China，Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China，Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China，Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China，Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China，Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China，Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060
Keywords:Chemotherapy-induced peripheral neuropathy, neuropathic pain, calcineurin, NFAT, inflammation, oxaliplatin.
Abstract:Objective: The aim of this study was to investigate the mechanism of oxaliplatin in the induction of
neuropathic pain as a symptom of Chemotherapy-Induced Peripheral Neuropathy (CIPN).
Methods: The CIPN rat model was induced with a one-time injection of oxaliplatin, and the paw withdrawal
response was determined using von Frey filaments. The Paw Withdrawal Threshold (PWT) value was recorded
and the Dorsal Horn (DH) and Dorsal Root Ganglion (DRG) tissues were collected. The mRNA and protein
levels of Calcineurin (CaN), Nuclear Factor of Activated T cells (NFAT), and other relevant cytokines were
determined. CaN and NFAT inhibition reagents, FK506 and 11R-VIVIT, were applied in order to investigate the
functions of the CaN/NFAT pathway in the neuropathic pain processes. The levels of the downstream inflammatory
cytokines, TNF-α and IL-1β, were assessed by ELISA.
Results: The application of oxaliplatin reduced the value of PWT by 4 times on days 7（4±1.33）and
14（5.13±3.07）compared with the control group(14±0.91; 13.67±0.76). After treatment, the CaN mRNA level
decreased and that of NFAT increased in DH and DRG tissues (P<0.05). However, treatment with FK506 and
11R-VIVIT decreased the value of PWT that had increased after oxaliplatin treatment. The expression of downstream
cytokines related to the CaN/NFAT pathway increased, including CCR2, COX2, p-ERK, and p-P38 (all
p<0.05). In addition, when the CaN/NFAT pathway was activated, the concentration of TNFα increased to
40pg/mg in DH tissues and 60pg/mg in DRG tissues compared with the control group, while the concentration
of IL-1β increased to over 60pg/mg in DH and DRG tissues.
Conclusion: It was the first time to prove that oxaliplatin-induced neuropathic pain was correlated to the activation
of the CaN/NFAT pathway in our rat model. This finding can provide a new direction to explore the
mechanism of oxaliplatin-induced neuropathic pain.
