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DNMT3a‐triggered downregulation of K 2p 1.1 gene in primary sensory neurons contributes to paclitaxel‐induced neuropathic pain
Author(s) -
Mao Qingxiang,
Wu Shaogen,
Gu Xiyao,
Du Shibin,
Mo Kai,
Sun Linlin,
Cao Jing,
Bekker Alex,
Chen Liyong,
Tao YuanXiang
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32155
Subject(s) - downregulation and upregulation , paclitaxel , dorsal root ganglion , neuropathic pain , hyperalgesia , medicine , pharmacology , chemotherapy , chemistry , nociception , receptor , gene , dorsum , anatomy , biochemistry
Antineoplastic drugs induce dramatic transcriptional changes in dorsal root ganglion (DRG) neurons, which may contribute to chemotherapy‐induced neuropathic pain. K 2p 1.1 controls neuronal excitability by setting the resting membrane potential. Here, we report that systemic injection of the chemotherapy agent paclitaxel time‐dependently downregulates the expression of K 2p 1.1 mRNA and its coding K 2p 1.1 protein in the DRG neurons. Rescuing this downregulation mitigates the development and maintenance of paclitaxel‐induced mechanical allodynia and heat hyperalgesia. Conversely, in the absence of paclitaxel administration, mimicking this downregulation decreases outward potassium current and increases excitability in the DRG neurons, leading to the enhanced responses to mechanical and heat stimuli. Mechanically, the downregulation of DRG K 2p 1.1 mRNA is attributed to paclitaxel‐induced increase in DRG DNMT3a, as blocking this increase reverses the paclitaxel‐induced the decrease of DRG K 2p 1.1 and mimicking this increase reduces DRG K 2p 1.1 expression. In addition, paclitaxel injection increases the binding of DNMT3a to the K 2p 1.1 gene promoter region and elevates the level of DNA methylation within this region in the DRG. These findings suggest that DNMT3a‐triggered downregulation of DRG K 2p 1.1 may contribute to chemotherapy‐induced neuropathic pain.