Hyperalgesia induced by spinal and peripheral hydrogen sulfide: Evidence for involvement of Cav3.2 T-type calcium channels

Hydrogen sulfide (H2S), a gasotransmitter, facilitates membrane currents through T-type Ca2+ channels, and intraplantar (i.pl.) administration of NaHS, a donor of H2S, 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(v)3.2 isoform of T-type Ca2+ channels contributed to the pronociceptive 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 Ca2+ channel inhibitor, and also Suppressed by pretreatment with i.t. and i.pl, zinc chloride, known to preferentially inhibit Ca(v)3.2 among T-type Ca2+ channel isoforms, respectively. Repeated i.t. administration of antisense oligodeoxynucleotides (ODNs) targeting rat Cav3.2, but not mismatch ODNs, caused silencing of Ca(v)3.2 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/H2S activates or sensitizes Ca(v)3.2 T-type Ca2+ channels expressed in the primary afferents and/or spinal nociceptive neurons, leading to sensitization of nociceptive processing and hyperalgesia. (C) 2008 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.