Early-life cisplatin exposure induces neuroinflammation and chemotherapy-induced neuropathic pain
Marlene Da Vitoria Lobo, Lydia Hardowar, Tameille Valentine, Lucy Tomblin, Charlotte Guest, Dhyana Sharma, Benjamin Dickins, Mark J. Paul‐Clark, Richard P. Hulse
Abstract
Chemotherapy-induced neuropathic pain (CINP) is a common adverse health-related comorbidity that manifests later in life in patients with paediatric cancer. 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 (NGF)-mediated neuroinflammation and nociceptor sensitisation. In a rat model of cisplatin-induced survivorship pain, cisplatin induced a neuroinflammatory environment in the dorsal root ganglia (DRG), demonstrated by NGF-positive macrophages infiltrating into the DRG. Cisplatin-treated CD11b- and F4/80-positive macrophages expressed more NGF compared to those treated with vehicle control. Mouse primary DRG sensory neuronal cultures demonstrated enhanced NGF-dependent TRPV1-mediated nociceptor activity after cisplatin treatment. Increased nociceptor activity was also observed when cultured mouse DRG neurons were treated with conditioned medium from cisplatin-activated macrophages. Elevated nociceptor activity was inhibited in a dose-dependent manner by an NGF-neutralising antibody. Intraperitoneal administration of the NGF-neutralising antibody reduced cisplatin-induced mechanical hypersensitivity and aberrant nociceptor intraepidermal nerve fibre density. These findings identify that a monocyte- or macrophage-driven NGF-TrkA pathway is a novel analgesic target for adult survivors of childhood cancer.