• Pain · Jul 2010

    Upregulation of Ca(v)3.2 T-type calcium channels targeted by endogenous hydrogen sulfide contributes to maintenance of neuropathic pain.

    • Tomoko Takahashi, Yuka Aoki, Kazumasa Okubo, Yumi Maeda, Fumiko Sekiguchi, Kenji Mitani, Hiroyuki Nishikawa, and Atsufumi Kawabata.
    • Division of Pharmacology & Pathophysiology, Kinki University School of Pharmacy, Higashi-Osaka 577-8502, Japan.
    • Pain. 2010 Jul 1;150(1):183-91.

    AbstractHydrogen sulfide (H(2)S) formed from l-cysteine by multiple enzymes including cystathionine-gamma-lyase (CSE) is now considered a gasotransmitter in the mammalian body. Our previous studies have shown that H(2)S activates/sensitizes Ca(v)3.2 T-type Ca(2+) channels, leading to facilitation of somatic and visceral nociception, and that CSE-derived endogenous H(2)S participates in inflammatory pain. Here, we show novel evidence for involvement of the endogenous H(2)S-Ca(v)3.2 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 beta-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 H(2)S, in the L5SNC rat. Intraplantar administration or topical application of mibefradil, a T-type Ca(2+) channel blocker, reversed hyperalgesia in the L5SNC rat. The protein levels of Ca(v)3.2, but not CSE, in the ipsilateral L4, L5 and L6 dorsal root ganglia were dramatically upregulated in the L5SNC rat. Finally, silencing of Ca(v)3.2 in DRG by repeated intrathecal administration of Ca(v)3.2-targeting siRNA significantly attenuated the neuropathic hyperalgesia in the L5SNC rat. In conclusion, our data suggest that Ca(v)3.2 T-type Ca(2+) channels in sensory neurons are upregulated and activated/sensitized by CSE-derived endogenous H(2)S after spinal nerve injury, contributing to the maintenance of neuropathic pain. We thus propose that Ca(v)3.2 and CSE could be targets for the development of therapeutic drugs for the treatment of neuropathic pain.Copyright 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

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