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.
Original language | English |
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Pages (from-to) | 2023-2036 |
Number of pages | 14 |
Journal | Journal of Clinical Investigation |
Volume | 124 |
Issue number | 5 |
Early online date | 17 Apr 2014 |
DOIs | |
Publication status | Published - 31 May 2014 |
Keywords
- FRACTALKINE RECEPTOR CX(3)CR1
- DEFICIENCY PROTECTS MICE
- PERIPHERAL NEUROPATHY
- SENSORY NEURONS
- MECHANICAL ALLODYNIA
- COLD HYPERALGESIA
- NERVOUS-SYSTEM
- KNOCKOUT MICE
- CATHEPSIN-S
- PACLITAXEL