Abstract
Hydrogen sulfide (H 2S), a gasotransmitter, facilitates membrane currents through T-type Ca 2+ channels, and intraplantar (i.pl.) administration of NaHS, a donor of H 2S, causes prompt hyperalgesia in rats. In this context, we asked whether intrathecal (i.t.) administration of NaHS could mimic the hyperalgesic effect of i.pl. NaHS in rats, and then examined if Ca v3.2 isoform of T-type Ca 2+ channels contributed to the pro-nociceptive effects of i.t. and i.pl. NaHS. Either i.t. or i.pl. administration of NaHS rapidly decreased nociceptive threshold in rats, as determined by the paw pressure method. The hyperalgesia caused by i.t. and i.pl. NaHS was abolished by co-administration of mibefradil, a pan-T-type Ca 2+ channel inhibitor, and also suppressed by pretreatment with i.t. and i.pl. zinc chloride, known to preferentially inhibit Ca v3.2 among T-type Ca 2+ channel isoforms, respectively. Repeated i.t. administration of antisense oligodeoxynucleotides (ODNs) targeting rat Ca v3.2, but not mismatch ODNs, caused silencing of Ca v3.2 protein in the dorsal root ganglia and spinal cord, and then attenuated the hyperalgesia induced by either i.t. or i.pl. NaHS. Our findings thus establish that spinal and peripheral NaHS/H 2S activates or sensitizes Ca v3.2 T-type Ca 2+ channels expressed in the primary afferents and/or spinal nociceptive neurons, leading to sensitization of nociceptive processing and hyperalgesia.
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