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

Chemotherapy-induced peripheral sensory neuropathy (CIPN) is a highly prevalent adverse health related comorbidity that manifests later in life in adult patients who have undergone paediatric cancer treatment with chemotherapeutic agents. Symptoms are typified by induction of neuropathic pain in a larger proportion of these patients. There is limited understanding of how this cisplatin induced sensory neuropathy develops and as a consequence current treatment approaches are not effective. The mechanisms that cause cisplatin-induced survivorship pain have yet to be elucidated; however, recent studies have indicated the involvement a key component, TrkA receptor signalling. The aim of this study was to investigate the effect of cisplatin mediated neuroinflammation and the dependence upon cisplatin induced nociceptor sensitisation upon nerve growth factor signalling. In a rodent model of cisplatin induced survivorship pain, there was a prominent induction of neuroinflammatory process in the dorsal root ganglia, demonstrated by infiltration of NGF positive CD45 positive macrophages. Isolated mouse splenocytes exposed to cisplatin led to increases in NGF expression. Primary cell cultures of sensory neurons from the dorsal root ganglia of neonatal mice treated with cisplatin demonstrated enhanced TRPV1 mediated nociceptor activity, which was NGF dependent. In addition, conditioned media from cisplatin treated splenocytes similarly increased nociceptor activity, which was inhibited in a dose dependent manner following NGF monoclonal antibody incubation. Administration of monoclonal NGF antibody invivo prevented cisplatin induced survivorship pain in mice depicted by reductions in mechanical hypersensitivity as well as suppression of cisplatin induced aberrant nociceptor intraepidermal nerve fibre density. These results indicate that cisplatin treatment induces nociceptor activation via NGF mediated neuroinflammation. The present findings provide a basis on which future studies into NGF/TrkA signalling inhibition may prove to have clinical significance as a therapy for CIPN in adult survivors of childhood cancer. ### Competing Interest Statement The authors have declared no competing interest.