title: 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.forename: Elizabeth A
authors.initials: EA
authors.lastname: Old
authors.forename: Suchita
authors.initials: S
authors.lastname: Nadkarni
authors.forename: John
authors.initials: J
authors.lastname: Grist
authors.forename: Clive
authors.initials: C
authors.lastname: Gentry
authors.forename: Stuart
authors.initials: S
authors.lastname: Bevan
authors.forename: Ki-Wook
authors.initials: KW
authors.lastname: Kim
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Mogg
authors.forename: Mauro
authors.initials: M
authors.lastname: Perretti
authors.forename: Marzia
authors.initials: M
authors.lastname: Malcangio
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000494:pharmacology; D000073883:CX3C Chemokine Receptor 1; D054428:Chemokine CX3CL1 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D006930:Hyperalgesia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D010146:Pain / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D014750:Vincristine / Q000009:adverse effects* / Q000494:pharmacology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000073883:CX3C Chemokine Receptor 1; D054428:Chemokine CX3CL1; C515539:Cx3cl1 protein, mouse; C471885:Cx3cr1 protein, mouse; D019707:Receptors, Chemokine; D014750:Vincristine
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