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

Monocytes expressing CX3CR1 orchestrate the development of vincristine-induced pain

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 1

Vincristine treatment induces mechanical allodynia and macrophage infiltration in the sciatic nerve.

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Vincristine treatment induces mechanical allodynia and macrophage infilt...
(A) Development of mechanical allodynia following VCR administration at 0.5 mg/kg/d i.p. for 2 cycles of 5 days each (days 0–4 and 7–11; black horizontal bars) (total dose 125 μg per mouse). Data are expressed as 50% of paw withdrawal thresholds (mean ± SEM; saline vehicle group, n = 8 mice; VCR group, n = 12 mice [day 24, n = 6]). ***P < 0.001 compared to baseline thresholds (B), ###P < 0.001 compared saline-treated thresholds, 2-way RM ANOVA, post-hoc Holm-Sidak test. (B) Significant monocyte-macrophage infiltration of the sciatic nerve during and after VCR cycles. The number of F4/80+ cells was counted in 104 μm2 boxes in sciatic nerve segments (mean ± SEM, n = 4 mice). ***P < 0.001 compared to saline control, 1-way ANOVA, post-hoc Tukey test. (C) Representative photomicrographs showing F4/80+ cells in sciatic nerve sections after 4-day treatment with saline or VCR. Scale bar: 200 μm. (D) No change in microglial cell numbers in the dorsal horn of the spinal cord during and after VCR cycles. The number of Iba1+cells was counted in 2.25 × 104 μm2 boxes (mean ± SEM, n = 4 mice per group). (E) Representative photomicrographs of Iba1+ cells in lumbar dorsal horn sections obtained after either saline or VCR treatment for 11 days. Scale bar: 100 μm; 20 μm (insets).