Oxaliplatin Regulates Chemotherapy Induced Peripheral Neuropathic Pain in the Dorsal Horn and Dorsal Root Ganglion via the Calcineurin/NFAT Pathway

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#136;4±1.33#137;and 14#136;5.13±3.07#137;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.