Involvement of inflammatory mediators in neuropathic pain caused by vincristine.
Elucidation of the mechanism of neuropathic pain caused by vincristine is required because long-term treatment with this anticancer agent often causes neuropathic pain. We refer to the involvement of inflammatory mediators in vincristine-induced neuropathic pain in this review. Several reports using rodents have shown that long-lasting neuropathic pain (mechanical allodynia) is caused by repeated systemic injection of vincristine. Vincristine damaged Schwann cells and DRG neurons in this model. Vincristine-induced macrophage infiltration in the peripheral nervous system (PNS) and macrophage-derived IL-6 elicited mechanical allodynia. These findings proved that inhibition of IL-6 function prevented neuropathic pain caused by vincristine. In the central nervous system (CNS), activation of microglia and astrocytes in the spinal cord were demonstrated after long-term vincristine treatment. TNF-alpha was upregulated in activated microglia and astrocytes, and inhibition of TNF-alpha function attenuated neuropathic pain caused by vincristine. These results suggest that vincristine induces macrophage infiltration to the damaged PNS, and that macrophage-derived inflammatory cytokines such as IL-6 elicits neuroinflammation. Signal transduction of pain from the PNS to the CNS activates microglia and astrocytes, and these activated glial cells release inflammatory cytokines such as TNF-alpha. In the CNS, these inflammatory cytokines have an important role in the neuropathic pain caused by vincristine. Immune-modulating agents that prevent activation of immune cells and/or the inhibitory agents of inflammatory cytokines could prevent the neuropathic pain caused by vincristine. These agents could increase the tolerability of vincristine when used for the treatment of leukemia and lymphoma.
Kiguchi
Norikazu
N
Department of Pharmacology, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-0012, Japan.
Maeda
Takehiko
T
Kobayashi
Yuka
Y
Saika
Fumihiro
F
Kishioka
Shiroh
S
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002490:Central Nervous System / Q000187:drug effects* / Q000276:immunology*; D018836:Inflammation Mediators / Q000502:physiology*; D008954:Models, Biological; D009437:Neuralgia / Q000139:chemically induced; D020078:Neurogenic Inflammation / Q000503:physiopathology*; D010146:Pain / Q000139:chemically induced* / Q000503:physiopathology; D017933:Peripheral Nervous System / Q000187:drug effects / Q000276:immunology; D014750:Vincristine / Q000633:toxicity*
D000970:Antineoplastic Agents; D018836:Inflammation Mediators; D014750:Vincristine