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Microglial P2Y12 Signaling Contributes to Cisplatin-induced Pain Hypersensitivity via IL-18-mediated Central Sensitization in the Spinal Cord

Administration of cisplatin and other chemotherapy drugs is crucial for treating tumors. However, cisplatin-induced pain hypersensitivity is still a critical clinical issue, and the underlying molecular mechanisms have remained unresolved to date. In this study, we found that repeated cisplatin treatments remarkedly upregulated the P2Y12 expression in the spinal cord. Expression of P2Y12 was predominant in the microglia. Pharmacological inhibition of P2Y12 expression markedly attenuated the cisplatin-induced pain hypersensitivity. Meanwhile, blocking the P2Y12 signal also suppressed cisplatin-induced microglia hyperactivity. Furthermore, the microglia Src family kinase/p38 pathway is required for P2Y12-mediated cisplatin-induced pain hypersensitivity via the proinflammatory cytokine IL-18 production in the spinal cord. Blocking the P2Y12/IL-18 signaling pathway reversed cisplatin-induced pain hypersensitivity, as well as activation of N-methyl-D-aspartate receptor and subsequent Ca2+-dependent signals. Collectively, our data suggest that microglia P2Y12-SFK-p38 signaling contributes to cisplatin-induced pain hypersensitivity via IL-18-mediated central sensitization in the spinal, and P2Y12 could be a potential target for intervention to prevent chemotherapy-induced pain hypersensitivity. PERSPECTIVE: Our work identified that P2Y12/IL-18 played a critical role in cisplatin-induced pain hypersensitivity. This work suggests that P2Y12/IL-18 signaling may be a useful strategy for the treatment of chemotherapy-induced pain hypersensitivity.

 

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The study found that the expression of P2Y12 in the spinal cord was upregulated by cisplatin treatments and predominantly in microglia, leading to pain hypersensitivity, which was reversed by blocking the P2Y12/IL-18 signaling pathway in the spinal cord, suggesting that P2Y12/IL-18 signaling may be a useful target for preventing chemotherapy-induced pain hypersensitivity.

 

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S1166 Cisplatin Cisplatin is an inorganic platinum complex, which is able to inhibit DNA synthesis by conforming DNA adducts in tumor cells. Cisplatin activates ferroptosis and induces autophagy.Solutions are unstable and should be fresh-prepared.DMSO is not recommended to dissolve platinum-based drugs, which can easily lead to drug inactivation.

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