Early life cisplatin exposure induces nerve growth factor mediated neuroinflammation and chemotherapy induced neuropathic pain

Chemotherapy-induced neuropathic pain (CINP) is a common adverse health related comorbidity that manifests later in life in paediatric cancer patients. Current analgesia is ineffective, aligning closely with our lack of understanding of CINP. The aim of this study was to investigate how cisplatin induces nerve growth factor mediated neuroinflammation and nociceptor sensitisation. In a rodent model of cisplatin induced survivorship pain, cisplatin induced a neuroinflammatory environment in the dorsal root ganglia (DRG) demonstrated by nerve growth factor (NGF) positive macrophages infiltrating into the DRG. Cisplatin treated CD11b/F480 positive macrophages expressed more NGF compared to vehicle treated. Primary DRG sensory neuronal cultures demonstrated enhanced NGF-dependent TRPV1 mediated nociceptor activity after cisplatin treatment. Increased nociceptor activity was also observed when cultured DRG neurons were treated with conditioned media from cisplatin activated macrophages. Elevated nociceptor activity was dose-dependently inhibited by a neutralising NGF antibody. Intraperitoneal administration of a NGF neutralising antibody reduced cisplatin-induced mechanical hypersensitivity and aberrant nociceptor intraepidermal nerve fibre density. These findings identify that a monocyte/macrophage driven NGF/TrkA pathway is a novel analgesic target for adult survivors of childhood cancer. To investigate the inflammatory response in dorsal root ganglia (DRG) after treatment with cisplatin and vehicle with the intention of dissecting the inflammatory processes influence on chemotherapy-induced peripheral neuropathies We performed gene expression profiling analysis of RNA-seq data obtained from 2 neonatal Wistar rats treated with vehicle (PBS) and 2 neonatal Wistar rats treated with cisplatin (Sigma-Aldrich; 0.3mg/kg). DRG's were isolated 16 days post-treatment. Differential gene expression was performed between DRGs isolated from vehicle compared with cisplatin treated rodents.