Targeting Upregulation of Neuronal IGF1 / IGF1R Signalling in the Spinal Cord Prevents Cisplatin‐Induced Peripheral Neuropathy in Mice

ABSTRACT Background Chemotherapy‐induced peripheral neuropathy (CIPN), characterised by a stocking‐glove distribution of numbness and pain, is a severe clinical challenge. Our previous study showed that overexpression of neuronal G protein‐coupled receptor kinase (GRK2) in the spinal dorsal horn (SDH) prevented cisplatin‐induced CIPN in mice. The underlying mechanism, however, remains unclear. This study aimed to explore the role of insulin‐like growth factor 1 (IGF1) in preventing CIPN through neuronal GRK2 in the SDH of mice. Methods CIPN model was established by intraperitoneally injecting cisplatin (23 mg/kg) in mice. Neuronal IGF1R or GRK2 in SDH was downregulated by intraspinally injecting an AAV vector delivering IGF1R or GRK2 shRNA with hSyn promoter. Mechanical allodynia and sensory deficits were assessed by von Frey test and adhesive removal test. The expression of IGF1, IGF1R and Iba1 was assessed by immunostaining. Neuroinflammation was assessed by real‐time PCR. The IGF1R and GRK2 levels were assessed by Western blot. Results Cisplatin chemotherapy induced a decrease of IGF1 and p‐IGF1R in SDH; intrathecal (i.t) injection of recombinant IGF1 (rIGF1) significantly prevented cisplatin‐induced mechanical allodynia, sensory deficit, and microglia activation and neuroinflammation in SDH. IGF1R was primarily localised within neurons (~81%). Downregulation of neuronal IGF1R (AAV‐shIGF1R) inhibited the preventive effect of i.t. rIGF1 on CIPN, and on the upregulation of GRK2 in SDH. Furthermore, downregulation of neuronal GRK2 in SDH inhibited the preventive effect of i.t. rIGF1 on CIPN. Conclusions I.t. injection of rIGF1 regulates neuronal GRK2 through neuronal IGF1R in SDH, alleviates microglial activation and neuroinflammation, thereby preventing cisplatin‐induced CIPN. Significance Statement This work elucidates the role of neuronal IGF1/IGF1R in the process of CIPN prevention and provides new animal‐based evidence for CIPN prevention by targeting neuronal IGF1/IGF1R in SDH.