Spinal dorsal horn IGF1 mediates the preventive effect of electroacupuncture on cisplatin-induced peripheral neuropathy via neuronal IGF1R in mice

Abstract Background Our previous study demonstrated that neuronal G protein-coupled receptor kinase (GRK2) upregulation alleviated chemotherapy-induced peripheral neuropathy (CIPN) in mice, which was characterized by numbness and pain in distal hind limbs. The neuronal GRK2 was identified as a mediator of electroacupuncture (EA) effects on CIPN. Given that spinal insulin-like growth factor 1 (IGF1), a known inducer of GRK2 in the peripheral neurons, decreases after oxaliplatin treatment in mice, this study is designed to investigate whether spinal IGF1 contributes to EA-mediated prevention of cisplatin-induced peripheral neuropathy via neuronal IGF1 receptor (IGF1R). Methods A total of 133 male C57BL/6 J mice were included in this study and randomly assigned to different experimental groups. The level of Igf1 mRNA was detected by Real-time PCR, the p-IGF1R protein level by Western blot, after EA treatment in cisplatin-treated mice. The cellular distribution of p-IGF1R in the spinal dorsal horn was observed by immunofluorescent staining. To study the role of neuronal IGF1R in EA preventing cisplatin-induced mechanical allodynia, sensory deficit, and microglia activation and neuroinflammation in the spinal cord of mice, the neuronal IGF1R was downregulated by intraspinal injection of an AAV vector delivering IGF1R shRNA with hSyn promotor (AAV-shIGF1R). Finally, the regulatory effect of EA on spinal GRK2 was assessed by Western blot in AAV-shIGF1R mice. Results Cisplatin treatment induced mechanical allodynia, sensory deficit, and a decrease of p-IGF1R in the spinal dorsal horn of mice. Immunofluorescence showed that p-IGF1R was localized within neurons (~ 82%), a small mount of microglia (~ 12%) and astrocytes (~ 4%). Cisplatin decreased NeuN + p-IGF1R + neurons in the spinal dorsal horn. EA treatment significantly alleviated cisplatin-induced mechanical allodynia, sensory deficit, and significantly increased the Igf1 mRNA and p-IGF1R level in the spinal cord. Neuronal IGF1R downregulation in the spinal dorsal horn significantly attenuated the preventive effect of EA on cisplatin-induced mechanical allodynia, sensory deficit, and spinal microglial activation and neuroinflammation in mice. Furthermore, neuronal IGF1R downregulation decreased the spinal GRK2 in cisplatin-treated mice after EA treatment. These findings suggest EA significantly alleviated CIPN symptoms by enhancing IGF1/IGF1R signaling and reducing microglial activation and neuroinflammation. Conclusion Spinal dorsal horn IGF1 contributes to the preventive effect of EA treatment against cisplatin-induced peripheral neuropathy through neuronal IGF1R signaling in mice. The enhanced neuronal IGF1/IGF1R signaling in the spinal cord presents a potential strategy for CIPN prevention.