Upregulation of Ca_v3.2 T-type calcium channels targeted by endogenous hydrogen sulfide contributes to maintenance of neuropathic pain

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• 作者：Tomoko Takahashi ; Yuka Aoki ; Kazumasa Okubo ; Yumi Maeda ; Fumiko Sekiguchi ; Kenji Mitani ; Hiroyuki Nishikawa ; Atsufumi Kawabata
• 关键词：Pain ; Neuropathic pain ; T-type calcium channel ; Hyperalgesia ; RNA interference ; Hydrogen sulfide
• 刊名：Pain
• 出版年：2010
• 出版时间：July 2010
• 年：2010
• 卷：150
• 期：1
• 页码：183-191
• 全文大小：1328 K

文摘

Hydrogen sulfide (H₂S) formed from l-cysteine by multiple enzymes including cystathionine-γ-lyase (CSE) is now considered a gasotransmitter in the mammalian body. Our previous studies have shown that H₂S activates/sensitizes Ca_v3.2 T-type Ca²⁺ channels, leading to facilitation of somatic and visceral nociception, and that CSE-derived endogenous H₂S participates in inflammatory pain. Here, we show novel evidence for involvement of the endogenous H₂S–Ca_v3.2 pathway in neuropathic pain. In the rat subjected to the right L5 spinal nerve cutting (L5SNC), a neuropathic pain model, i.p. administration of dl-propargylglycine (PPG) and β-cyanoalanine, irreversible and reversible CSE inhibitors, respectively, strongly suppressed the neuropathic hyperalgesia/allodynia. The anti-hyperalgesic effect of PPG was reversed by intraplantar administration of NaHS, a donor for H₂S, in the L5SNC rat. Intraplantar administration or topical application of mibefradil, a T-type Ca²⁺ channel blocker, reversed hyperalgesia in the L5SNC rat. The protein levels of Ca_v3.2, but not CSE, in the ipsilateral L4, L5 and L6 dorsal root ganglia were dramatically upregulated in the L5SNC rat. Finally, silencing of Ca_v3.2 in DRG by repeated intrathecal administration of Ca_v3.2-targeting siRNA significantly attenuated the neuropathic hyperalgesia in the L5SNC rat. In conclusion, our data suggest that Ca_v3.2 T-type Ca²⁺ channels in sensory neurons are upregulated and activated/sensitized by CSE-derived endogenous H₂S after spinal nerve injury, contributing to the maintenance of neuropathic pain. We thus propose that Ca_v3.2 and CSE could be targets for the development of therapeutic drugs for the treatment of neuropathic pain.