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Promoter demethylation of cystathionine-β-synthetase gene contributes to inflammatory pain in rats

Qi, Feihua,1; Zhou, Youlanga,b,1; Xiao, Yingb; Tao, Jinb; Gu, Jianguoc; Jiang, Xinghongb; Xu, Guang-Yina,b,*

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doi: 10.1016/j.pain.2012.07.031
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Summary Epigenetic regulation of cystathionine-β-synthetase expression contributes to inflammatory hyperalgesia. H2S increases tetrodotoxin-resistant sodium channel currents via protein kinase A signaling pathway in dorsal root ganglia neurons.

Hydrogen sulfide (H2S), an endogenous gas molecule synthesized by cystathionine-β-synthetase (CBS), is involved in inflammation and nociceptive signaling. However, the molecular and epigenetic mechanisms of CBS-H2S signaling in peripheral nociceptive processing remain unknown. We demonstrated that peripheral inflammation induced by intraplantar injection of complete Freund adjuvant significantly up-regulated expression of CBS at both protein and mRNA levels in rat dorsal root ganglia (DRG). The CBS inhibitors hydroxylamine and aminooxyacetic acid attenuated mechanical hyperalgesia in a dose-dependent manner and reversed hyperexcitability of DRG neurons in inflamed rats. Intraplantar administration of NaHS (its addition mimics CBS production of H2S) or L-cysteine in healthy rats elicited mechanical hyperalgesia. Application of NaHS in vitro enhanced excitability and tetrodotoxin (TTX)-resistant sodium current of DRG neurons from healthy rats, which was attenuated by pretreatment of protein kinase A inhibitor H89. Methylation-specific PCR and bisulfite sequencing demonstrated that promoter region of cbs gene was less methylated in DRG samples from inflamed rats than that from controls. Peripheral inflammation did not alter expression of DNA methyltransferase 3a and 3b, the 2 major enzymes for DNA methylation, but led to a significant up-regulation of methyl-binding domain protein 4 and growth arrest and DNA damage inducible protein 45α, the enzymes involved in active DNA demethylation. Our findings suggest that epigenetic regulation of CBS expression may contribute to inflammatory hyperalgesia. H2S seems to increase TTX-resistant sodium channel current, which may be mediated by protein kinase A pathway, thus identifying a potential therapeutic target for the treatment of chronic pain.

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

aJiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong 226001, PR China

bInstitute of Neuroscience, Department of Neurobiology and Psychology, Key Laboratory of Pain Research and Therapy, Soochow University, Suzhou 215123, PR China

cDepartment of Anesthesiology and the Graduate Program in Neuroscience, University of Cincinnati College of Medicine, P.O. Box 670531, 231 Albert Sabin Way, Cincinnati, OH 45267-0531, USA

*Corresponding author at: Institute of Neuroscience, Department of Neurobiology and Psychology, Key Laboratory of Pain Research and Therapy, Soochow University, Suzhou 215123, PR China. Tel.: +86 512 6588 2817; fax: +86 512 6588 3602.

E-mail address:guangyinxu@suda.edu.cn

1These authors contributed equally to this article, and both should be considered first author.

Article history: Received 14 January 2012; Received in revised form 27 July 2012; Accepted 30 July 2012.

© 2013 Lippincott Williams & Wilkins, Inc.
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