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

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

doi:10.1016/j.bbi.2019.10.018

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

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

Research output: Contribution to journal › Article › peer-review

23 Citations (Scopus)

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.

Original language	English
Pages (from-to)	248-259
Number of pages	12
Journal	Brain Behavior and Immunity
Volume	83
Early online date	24 Oct 2019
DOIs	https://doi.org/10.1016/j.bbi.2019.10.018
Publication status	Published - 1 Jan 2020

Keywords

Blood-spinal cord barrier
Cathepsin S
Chemotherapy-induced neuropathic pain
Endothelium
Infiltration
Monocytes
Permeability
Tight Junctions
Vincristine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.bbi.2019.10.018Licence: CC BY

Cite this

@article{ac848d29ae2547f18d0961d3cd9c9f3d,

title = "Changes in vascular permeability in the spinal cord contribute to chemotherapy-induced neuropathic pain",

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.",

keywords = "Blood-spinal cord barrier, Cathepsin S, Chemotherapy-induced neuropathic pain, Endothelium, Infiltration, Monocytes, Permeability, Tight Junctions, Vincristine",

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

year = "2020",

month = jan,

day = "1",

doi = "10.1016/j.bbi.2019.10.018",

language = "English",

volume = "83",

pages = "248--259",

journal = "Brain Behavior and Immunity",

issn = "0889-1591",

publisher = "ACADEMIC PRESS INC",

}

TY - JOUR

T1 - Changes in vascular permeability in the spinal cord contribute to chemotherapy-induced neuropathic pain

AU - Montague-Cardoso, Karli

AU - Pitcher, Thomas

AU - Chisolm, Kim

AU - Salera, Giorgia

AU - Lindstrom, Erik

AU - Hewitt, Ellen

AU - Solito, Egle

AU - Malcangio, Marzia

PY - 2020/1/1

Y1 - 2020/1/1

N2 - 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.

AB - 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.

KW - Blood-spinal cord barrier

KW - Cathepsin S

KW - Chemotherapy-induced neuropathic pain

KW - Endothelium

KW - Infiltration

KW - Monocytes

KW - Permeability

KW - Tight Junctions

KW - Vincristine

UR - http://www.scopus.com/inward/record.url?scp=85074414078&partnerID=8YFLogxK

U2 - 10.1016/j.bbi.2019.10.018

DO - 10.1016/j.bbi.2019.10.018

M3 - Article

SN - 0889-1591

VL - 83

SP - 248

EP - 259

JO - Brain Behavior and Immunity

JF - Brain Behavior and Immunity

ER -

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

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this