Neuroinflammation induces nerve growth factor dependent nociceptor sensitisation in a neonatal rodent model of platinum-based chemotherapy induced neuropathic pain

Abstract

Chemotherapy-induced neuropathic pain (CINP) is a common adverse health related comorbidity that manifests later in life in paediatric patients treated for cancer. CIPN pathology progressively develops over time resulting in a delayed but long-lasting neuropathic pain. Current analgesic strategies are ineffective, aligning closely with our lack of understanding of CINP. Recent studies have indicated alterations in sensory neuronal maturation as component 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, there was a significant infiltration of nerve growth factor positive macrophages into the dorsal root ganglia (DRG), demonstrating a robust neuroinflammatory response. Additionally, it was observed that CD11b/F480 positive monocyte/macrophages challenged with cisplatin expressed more NGF. Additionally, DRG derived primary sensory neuron cultures from neonatal mice demonstrated enhanced NGF-dependent TRPV1 mediated nociceptor activity after cisplatin treatment. Increased nociceptor activity was also observed when cultured neurons were treated with conditioned media from cisplatin activated monocyte/macrophages. This elevated nociceptor activity was dose-dependently inhibited by a neutralising monoclonal antibody to NGF. Intraperitoneal administration of NGF neutralising antibody significant reduction in mechanical hypersensitivity was given to mice with cisplatin-induced juvenile survivorship pain there was a as well as suppression of cisplatin induced aberrant nociceptor intraepidermal nerve fibre density. These findings identify the NGF/TrkA signalling pathway as a potential novel therapeutic target for analgesia in adult survivors of childhood cancer.