Ten-eleven translocation 1 participates in oxaliplatin-induced neuropathic pain in mice by regulating miR-30b-5p/Nav1.6 signaling

Abstract

Abstract Background Chemotherapy-induced neuropathic pain refers to a pathological condition of pain that arises as a dose-dependent adverse effect, potentially hindering or obstructing the efficacy of cancer treatment. Oxaliplatin (OXA) is a chemotherapeutic agent belonging to the third generation of platinum-based compounds. Our previous investigation demonstrated the involvement of miR-30b-5p in the development of oxaliplatin-induced neuropathic pain in rats, specifically through the regulation of the voltage-gated sodium channel Nav1.6. Additionally, Ten-eleven translocation methylcytosine dioxygenase 1 (TET1) has been identified as a significant contributor to gene regulation. Here, we investigated the effects of TET1 on neuropathic pain and explored whether TET1 is involved in oxaliplatin -induced pain through miR-30b-5p/Nav1.6 signaling. Methods The chemotherapy-induced peripheral neuropathy model was established using an intraperitoneal injection of OXA. TET1 Lentiviral Activation Particles were microinjected to overexpress TET1. AAV5-CMV-bGlobin-Cre-eGfp were microinjected to decrease TET1 in Tet1flox/flox mice dorsal root ganglions (DRGs). Then, we detect miR-30b-5p and Nav1.6 expression, neuronal excitability, and pain behavior. Results We found that oxaliplatin decreased the TET1 expression in the DRGs and led to neuropathic pain symptoms by upregulating the Nav1.6 expression via modulating the methylation site in the Mir30b promoter. Simulating the decrease of TET1 in DRGs significantly reduced the level of DNA hydroxymethylation and led to pain-like behaviors. Conversely, blocking the decrease in TET1 reversed the oxaliplatin -induced miR-30b-5p reduction and attenuated the increase in Nav1.6 in the affected DRGs, thus alleviating oxaliplatin -induced pain hypersensitivities. Conclusion Our findings indicated that TET1 insufficiency was implicated in the development of chemotherapy-induced peripheral neuropathy via the modulation of Nav1.6 expression in primary sensory neurons, which was mediated by inadequate demethylation of Mir30b.