Inhibition of T-type calcium channels and hydrogen sulfide-forming enzyme reverses paclitaxel-evoked neuropathic hyperalgesia in rats

Hydrogen sulfide (H2S), a gasotransmitter, facilitates pain sensation by targeting Cav3.2 T-type calcium channels. The H2S/Cav3.2 pathway appears to play a role in the maintenance of surgically evoked neuropathic pain. Given evidence that chemotherapy-induced neuropathic pain is blocked by ethosuximide, known to block T-type calcium channels, we examined if more selective T-type calcium channel blockers and also inhibitors of cystathionine-γ–lyase (CSE), a major H2S-forming enzyme in the peripheral tissue, are capable of reversing the neuropathic pain evoked by paclitaxel, an anti-cancer drug. It was first demonstrated that T-type calcium channel blockers, NNC 55-0396, known to inhibit Cav3.1, and mibefradil inhibited T-type currents in Cav3.2-transfected HEK293 cells. Repeated systemic administration of paclitaxel caused delayed development of mechanical hyperalgesia, which was reversed by single intraplantar administration of NNC 55-0396 or mibefradil, and by silencing of Cav3.2 by antisense oligodeoxynucleotides. Systemic administration of dl-propargylglycine and β-cyanoalanine, irreversible and reversible inhibitors of CSE, respectively, also abolished the established neuropathic hyperalgesia. In the paclitaxel-treated rats, upregulation of Cav3.2 and CSE at protein levels was not detected in the dorsal root ganglia (DRG), spinal cord or peripheral tissues including the hindpaws, whereas H2S content in hindpaw tissues was significantly elevated. Together, our study demonstrates the effectiveness of NNC 55-0396 in inhibiting Cav3.2, and then suggests that paclitaxel-evoked neuropathic pain might involve the enhanced activity of T-type calcium channels and/or CSE in rats, but not upregulation of Cav3.2 and CSE at protein levels, differing from the previous evidence for the neuropathic pain model induced by spinal nerve cutting in which Cav3.2 was dramatically upregulated in DRG.

Graphical AbstractHighlights▶We examine roles of Cav3.2 T-type calcium channels and H2S in paclitaxel-evoked neuropathy. ▶T-type channel inhibitors or Cav3.2 knockdown reverses the neuropathic pain. ▶Inhibitors of an H2S-forming enzyme abolish the neuropathic hyperalgesia. ▶Paclitaxel elevates H2S levels in the hindpaw. ▶The neuropathic pain involves the hyperactivity of the T-type channel/H2S pathway.