Hydrogen 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.