Engagement of MicroRNA-155 in Exaggerated Oxidative Stress Signal and TRPA1 in the Dorsal Horn of the Spinal Cord and Neuropathic Pain During Chemotherapeutic Oxaliplatin

Abstract

Oxaliplatin (OXL) is a third-generation chemotherapeutic agent commonly used to treat metastatic digestive tumors, but one of the main limiting complications of OXL is painful peripheral neuropathy. The present study was to examine the inhibitory effects of blocking microRNA-155 (miR-155) in the dorsal horn of the spinal cord on neuropathic pain induced by OXL in rats and the underlying mechanisms. Behavioral test was performed to examine mechanical pain and cold sensitivity in rats. Real-time RT-PCR and ELISA were employed to determine miR-155 and products of oxidative stress 8-isoprostaglandin F2α (8-iso PGF2α) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the dorsal horn. Western blot analysis was used to examine expression of Nrf2-antioxidant response element (Nrf2-ARE), NADPH oxidases (NOXs), and transient receptor potential ankyrin 1 (TRPA1). In results, intrathecal administration of miR-155 inhibitor attenuated mechanical allodynia and cold hyperalgesia in rats with OXL therapy and this was accompanied with restoring of impaired Nrf2-ARE in the dorsal horn. A blockade of miR-155 also attenuated expression of NOX subtype 4 (NOX4) and thereby decreased the levels of 8-iso PGF2α/8-OHdG in the dorsal horn of OXL rats. In addition, inhibiting NOX4 decreased products of oxidative stress in the dorsal horn and attenuated upregulation of TRPA1 induced by OXL. In conclusion, data show the critical role of miR-155 in regulating OXL-induced neuropathic pain likely via oxidative stress-TRPA1 signal pathway, indicating that inhibition of miR-155 has potential benefits in preventing neuropathic pain development during intervention of OXL.