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Monocytes expressing CX3CR1 orchestrate the development of vincristine-induced pain
Elizabeth A. Old, … , Mauro Perretti, Marzia Malcangio
Elizabeth A. Old, … , Mauro Perretti, Marzia Malcangio
Published April 17, 2014
Citation Information: J Clin Invest. 2014;124(5):2023-2036. https://doi.org/10.1172/JCI71389.
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Research Article Neuroscience Article has an altmetric score of 19

Monocytes expressing CX3CR1 orchestrate the development of vincristine-induced pain

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Abstract

A major dose-limiting side effect associated with cancer-treating antineoplastic drugs is the development of neuropathic pain, which is not readily relieved by available analgesics. A better understanding of the mechanisms that underlie pain generation has potential to provide targets for prophylactic management of chemotherapy pain. Here, we delineate a pathway for pain that is induced by the chemotherapeutic drug vincristine sulfate (VCR). In a murine model of chemotherapy-induced allodynia, VCR treatment induced upregulation of endothelial cell adhesion properties, resulting in the infiltration of circulating CX3CR1+ monocytes into the sciatic nerve. At the endothelial-nerve interface, CX3CR1+ monocytes were activated by the chemokine CX3CL1 (also known as fractalkine [FKN]), which promoted production of reactive oxygen species that in turn activated the receptor TRPA1 in sensory neurons and evoked the pain response. Furthermore, mice lacking CX3CR1 exhibited a delay in the development of allodynia following VCR administration. Together, our data suggest that CX3CR1 antagonists and inhibition of FKN proteolytic shedding, possibly by targeting ADAM10/17 and/or cathepsin S, have potential as peripheral approaches for the prophylactic treatment of chemotherapy-induced pain.

Authors

Elizabeth A. Old, Suchita Nadkarni, John Grist, Clive Gentry, Stuart Bevan, Ki-Wook Kim, Adrian J. Mogg, Mauro Perretti, Marzia Malcangio

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Figure 2

Macrophage depletion prevents vincristine-induced allodynia.

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Macrophage depletion prevents vincristine-induced allodynia.
(A) LCL pre...
(A) LCL pretreatment prevents the development of VCR-induced allodynia. LCL (arrows; two 100 μl/10 g injections of 5 mg/ml LCL in PBS i.p.) was injected on day 3 and 1 before VCR (0.5 mg/kg/d i.p. from day 0 to 4; black horizontal bars). Data are expressed as 50% of paw withdrawal thresholds (mean ± SEM) (first VCR cycle, n = 9–11 mice; second VCR cycle, n = 4–6 mice). ***P < 0.001 compared to baseline thresholds, ###P < 0.001 compared to saline vehicle, †††P < 0.001 compared to PBS+VCR, 2-way RM ANOVA, post-hoc Holm-Sidak test. (B) Representative photomicrographs demonstrating that LCL prevents monocyte-macrophage (F4/80+ cell) infiltration in the sciatic nerve by the end of the first VCR cycle (days 0–4) but not the second VCR cycle (days 7–11). Scale bar: 200 μm. (C and D) The number of F4/80+ cells was counted in 104 μm2 boxes in sciatic nerve segments (mean ± SEM, n = 4 mice per group). ***P < 0.001, 1-way ANOVA, post-hoc Tukey test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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