Upregulation of Nav1.6 Mediated by the p38 MAPK Pathway in the Dorsal Root Ganglia Contributes to Cancer-Induced Bone Pain in Rats

Mingxue Lin; Xiaohui Chen; Shuyan Wu; Pinzhong Chen; Haiyang Wan; Simeng Ma; Na Lin; Yanling Liao; Ting Zheng; Jundan Jiang; Xiaochun Zheng

doi:10.3390/cells11213375

Upregulation of Na_v1.6 Mediated by the p38 MAPK Pathway in the Dorsal Root Ganglia Contributes to Cancer-Induced Bone Pain in Rats

Cells. 2022 Oct 26;11(21):3375. doi: 10.3390/cells11213375.

Authors

Mingxue Lin¹, Xiaohui Chen¹, Shuyan Wu¹, Pinzhong Chen¹, Haiyang Wan², Simeng Ma³, Na Lin¹, Yanling Liao¹, Ting Zheng¹, Jundan Jiang¹, Xiaochun Zheng^{1

4}

Affiliations

¹ Department of Anesthesiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou 350000, China.
² Department of Anesthesiology, First Affiliated Hospital of Yangtze University, First People's Hospital of Jingzhou, Jingzhou 434000, China.
³ Fujian Provincial Maternity and Children's Hospital, Fuzhou 350000, China.
⁴ Fujian Emergency Medical Center, Fujian Provincial Key Laboratory of Critical Care Medicine, Fuzhou 350000, China.

Abstract

Cancer-induced bone pain (CIBP) occurs frequently among advanced cancer patients. Voltage-gated sodium channels (VGSCs) have been associated with chronic pain, but how VGSCs function in CIBP is poorly understood. Here, we aimed to investigate the specific role of VGSCs in the dorsal root ganglia (DRGs) in CIBP. A CIBP rat model was generated by the intratibial inoculation of MRMT-1 breast carcinoma cells. Transcriptome sequencing was conducted to assess the gene expression profiles. The expression levels of key genes and differentiated genes related to activated pathways were measured by Western blotting and qPCR. We implanted a catheter intrathecally for the administration of lentivirus and drugs. Then, the changes in the mechanical withdrawal threshold (MWT) were measured. We identified 149 differentially expressed mRNAs (DEmRNAs) in the DRGs of CIBP model rats. The expression of Na_v1.6, which was among these DEmRNAs, was significantly upregulated. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of the DEmRNAs showed that they were mainly enriched in the mitogen-activated protein kinase (MAPK) pathway. The decrease in MWT induced by bone cancer was attenuated by Na_v1.6 knockdown. Western blot analysis revealed that a p38 inhibitor decreased the expression of Na_v1.6 and attenuated pain behavior. Our study shows that the upregulation of Na_v1.6 expression by p38 MAPK in the DRGs of rats contributes to CIBP.

Keywords: MAPK pathway; Nav1.6; RNA-seq; cancer-induced bone pain; dorsal root ganglion.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone Neoplasms / complications
Bone Neoplasms / metabolism
Cancer Pain* / genetics
Cancer Pain* / metabolism
Ganglia, Spinal / metabolism
NAV1.6 Voltage-Gated Sodium Channel* / genetics
NAV1.6 Voltage-Gated Sodium Channel* / metabolism
Pain / genetics
Pain / metabolism
Rats
Rats, Sprague-Dawley
Up-Regulation
Voltage-Gated Sodium Channels / metabolism
p38 Mitogen-Activated Protein Kinases* / metabolism

Substances

p38 Mitogen-Activated Protein Kinases
Voltage-Gated Sodium Channels
Scn8a protein, rat
NAV1.6 Voltage-Gated Sodium Channel

Grants and funding

This research was supported by the National Natural Science Foundation of China (grant no. 82171186 and 82001166); the Joint Funds for the Innovation of Science and Technology, Fujian Province (grant nos. 2019Y9028 and 2019Y9023); the Medical Innovation Project of Fujian Province (grant no. 2020CXB002); and the Natural Science Foundation of Fujian Province (grant nos. 2021J01366 and 2022J011009).