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

Lobo, M.D.V., Hardowar, L., Valentine, T., Tomblin, L., Guest, C., Sharma, D., Dickins, B., Paul-Clark, M. and Hulse, R.P. ORCID: 0000-0002-5193-9822, 2024. Early life cisplatin exposure induces nerve growth factor mediated neuroinflammation and chemotherapy induced neuropathic pain. Disease Models and Mechanisms. ISSN 1754-8403 (Forthcoming)

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Abstract

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.

Item Type:	Journal article
Publication Title:	Disease Models and Mechanisms
Creators:	Lobo, M.D.V., Hardowar, L., Valentine, T., Tomblin, L., Guest, C., Sharma, D., Dickins, B., Paul-Clark, M. and Hulse, R.P.
Publisher:	Company of Biologists
Date:	14 October 2024
ISSN:	1754-8403
Identifiers:	Number Type 2253579 Other
Divisions:	Schools > School of Science and Technology
Record created by:	Laura Ward
Date Added:	15 Oct 2024 14:51
Last Modified:	15 Oct 2024 14:51
URI:	https://irep.ntu.ac.uk/id/eprint/52418

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