INHIBITION OF T-TYPE CALCIUM CHANNELS AND HYDROGEN SULFIDE-FORMING ENZYME REVERSES PACLITAXEL-EVOKED NEUROPATHIC HYPERALGESIA IN RATS

摘要

Hydrogen sulfide (H_2S), a gasotransmitter, facilitates pain sensation by targeting Ca_v3.2 T-type calcium channels. The H_2S/Ca_v3.2 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 cystathio-nine-gamma-lyase (CSE), a major H_2S-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 Ca_v3.1, and mibefradil inhibited T-type currents in Ca_v3.2-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 Ca_v3.2 by antisense oligodeoxynucleotides. Systemic administration of dl-propargylglycine and beta-cyanoalanine, irreversible and reversible inhibitors of CSE, respectively, also abolished the established neuropathic hyperalgesia. In the paclitaxel-treated rats, upregulation of Ca_v3.2 and CSE at protein levels was not detected in the dorsal root ganglia (DRG), spinal cord or peripheral tissues including the hindpaws, whereas H_2S content in hindpaw tissues was significantly elevated. Together, our study demonstrates the effectiveness of NNC 55-0396 in inhibiting Ca_v3.2, 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 Ca_v3.2 and CSE at protein levels, differing from the previous evidence for the neuropathic pain model induced by spinal nerve cutting in which Ca_v3.2 was dramatically upregulated in DRG.