期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 124, 期 5, 页码 2023-2036出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI71389
关键词
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资金
- BBSRC CASE PhD studentship - Eli Lilly [BB/H531335/1]
- William Harvey Research Foundation
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.
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