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Changes in vascular permeability in the spinal cord contribute to chemotherapy-induced neuropathic pain

Research output: Contribution to journalArticle

Karli Montague-Cardoso, Thomas Pitcher, Kim Chisolm, Giorgia Salera, Erik Lindstrom, Ellen Hewitt, Egle Solito, Marzia Malcangio

Original languageEnglish
Pages (from-to)248-259
Number of pages12
JournalBrain Behavior and Immunity
Volume83
Early online date24 Oct 2019
DOIs
Accepted/In press23 Oct 2019
E-pub ahead of print24 Oct 2019
Published1 Jan 2020

King's Authors

Abstract

Chemotherapy-induced neuropathic pain is a dose-limiting side effect of many cancer therapies due to their propensity to accumulate in peripheral nerves, which is facilitated by the permeability of the blood-nerve barrier. Preclinically, the chemotherapy agent vincristine (VCR) activates endothelial cells in the murine peripheral nervous system and in doing so allows the infiltration of monocytes into nerve tissue where they orchestrate the development of VCR-induced nociceptive hypersensitivity. In this study we demonstrate that VCR also activates endothelial cells in the murine central nervous system, increases paracellular permeability and decreases trans endothelial resistance. In in vivo imaging studies in mice, VCR administration results in trafficking of inflammatory monocytes through the endothelium. Indeed, VCR treatment affects the integrity of the blood-spinal cord-barrier as indicated by Evans Blue extravasation, disrupts tight junction coupling and is accompanied by the presence of monocytes in the spinal cord. Such inflammatory monocytes (Iba-1+ CCR2+ Ly6C+ TMEM119- cells) that infiltrate the spinal cord also express the pro-nociceptive cysteine protease Cathepsin S. Systemic treatment with a CNS-penetrant, but not a peripherally-restricted, inhibitor of Cathepsin S prevents the development of VCR-induced hypersensitivity, suggesting that infiltrating monocytes play a functional role in sensitising spinal cord nociceptive neurons. Our findings guide us towards a better understanding of central mechanisms of pain associated with VCR treatment and thus pave the way for the development of innovative antinociceptive strategies.

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