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Papers of the Week

Papers: 15 Jul 2023 - 21 Jul 2023

Basic Science

Animal Studies, Molecular/Cellular, Neurobiology

Cancer Pain, Neuropathic Pain

2023 Jul 13

Toxicol Lett


MAPK-ERK-CREB signaling pathway upregulates Nav1.6 in oxaliplatin-induced neuropathic pain in the rat.


Shao J, Yu W, Wei W, Wang S, Zheng Z, Li L, Sun Y, Zhang J, Li Z, Ren X, Zang W, Cao J


The voltage-gated sodium channel subtype Nav1.6 is involved in the electrophysiological changes of primary sensory neurons that occur in oxaliplatin-induced neuropathic pain, but its regulatory mechanism remains unclear. In this study, Western blot, RT-qPCR, immunofluorescence staining, chromatin immunoprecipitation were used to prove the mechanism of MAPK-ERK-CREB signaling pathway participating in oxaliplatin-induced neuropathic pain by regulating Nav1.6. The results showed that p-Raf1 and p-ERK, key molecules in MAPK/ERK pathway, and Nav1.6 were significantly increased in DRGs of oxaliplatin-induced neuropathic pain rats. Inhibition of p-Raf1 and p-ERK respectively not only reduced the expression of Nav1.6 protein in DRGs of OXA rats, but also caused a decrease in Nav1.6 mRNA, which led us to further explore the transcription factor CREB regulated by MAPK/ERK pathway. Results showed that CREB was co-distributed with Nav1.6. Inhibition of CREB resulted in decreased mRNA and protein expression of Nav1.6, and alleviated oxaliplatin-induced neuropathic pain. A chromatin immunoprecipitation experiment proved that OXA caused p-CREB to directly bind to the promoter region of Scn8A, which is the encoding gene for Nav1.6, and promote the transcription of Scn8A. In summary, in this study, we found that oxaliplatin can activate the MAPK/ERK pathway, which promotes the expression and activation of CREB and leads to an increase in Scn8A transcription, and then leads to an increase in Nav1.6 protein expression to enhance neuronal excitability and cause pain. This study provides an experimental basis for the molecular mechanism of sodium channel regulation in oxaliplatin-induced neuropathic pain.