Hydrogen sulfide as a novel nociceptive messenger

Abstract

Hydrogen sulfide (H(2)S), an endogenous gasotransmitter, modulates various biological events such as inflammation in the mammalian body. The present study investigated possible involvement of H(2)S in peripheral nociceptive processing. Intraplantar (i.pl.) administration of NaHS, a H(2)S donor, produced prompt hyperalgesia in rats, accompanied by expression of Fos in the spinal dorsal horn. The H(2)S-evoked hyperalgesia was blocked by 5,5'-dithio-bis-(2-nitrobenzoic acid) (DTNB), an oxidizing agent, or ethosuximide and mibefradil, T-type Ca(2+) channel inhibitors. L-Cysteine, an endogenous source for H(2)S, given i.pl., also elicited hyperalgesia, an effect being abolished by DL-propargylglycine (PPG) and beta-cyanoalanine (BCA), inhibitors of cystathionine-gamma-lyase, a H(2)S synthesizing enzyme. PPG and/or BCA partially inhibited the hyperalgesia induced by i.pl. lipopolysaccharide, an effect being reversed by i.pl. NaHS. In the patch-clamp study using undifferentiated NG108-15 cells that express T-type, but not other types, of Ca(2+) channels, NaHS enhanced the currents through the T-type channels, an effect being blocked by DTNB. Thus, H(2)S appears to function as a novel nociceptive messenger through sensitization of T-type Ca(2+) channels in the peripheral tissues, particularly during inflammation.

Targeting Calcium Channels to Block Tumor Vascularization

“…The finding that DLpropargylglycine (PPG) and β-cyanoalanine, two CSE inhibitors, abolish the L-cysteine-induced hyperalgesia and attenuate the lipopolysaccharid-induced hyperalgesia, an effect reversed by NaHS, supports these observations [43,44]. Moreover, mibefradil suppressed the phosphorylation of ERK induced by the infusion of NaHS, a pronociceptive stimulus in the pancreatic duct, albeit at higher concentrations than those reported above (500 nM/rat) [46].…”

“…Furthermore, both intraplantar (1 nM/paw) and intratechal (0.01-0.1 nM/animal) administration of NaHS caused a prompt hyperalgesia in rats, an effect that was abolished by mibefradil, ZnCl2, or antisense oligodeoxynucleotides (ODNs) selectively targeting rat CaV3.2 [43][44][45]. The finding that DLpropargylglycine (PPG) and β-cyanoalanine, two CSE inhibitors, abolish the L-cysteine-induced hyperalgesia and attenuate the lipopolysaccharid-induced hyperalgesia, an effect reversed by NaHS, supports these observations [43,44].…”

“…A redox modulation of CaV3.2 has been proposed, since NaHS increases the amplitude of T-type Ca 2+ currents in a neuroblastoma cell line without affecting their kinetics. This effect was reversed by the oxidizing agent, 5,5′dithio-bis(2-nitrobenzoic acid) (DTNB), and mimicked by the reducing compound, dithiothreitol (DTT) [44]. It should be pointed out that the elevation in the density of T-type Ca 2+ currents was observed at 0.5-1.5 mM NaHS, i.e.…”

Gasotransmitters in Vascular Complications of Diabetes

“…H 2 S has mainly been reported to increase pain sensitivity via several proposed modes of action (95). These include sensitization of voltage-gated sodium and calcium channels (95-97) and/or suppression of potassium channels.…”

T-type Calcium Channels: Functional Regulation and Implication in Pain Signaling

“…This notion is consistent with our finding that not only intraplantar but also intrathecal administration of NaHS, a donor of H 2 S, caused hyperalgesia in rats, an effect blocked by a T-channel blocker or by silencing of the Ca v 3.2 gene (6). Activation/sensitization of Tchannels by endogenous H 2 S formed by CSE may be involved in inflammatory hyperalgesia because inhibitors of T-channels and CSE, an H 2 S-forming enzyme, prevent the development of inflammatory hyperalgesia caused by intraplantar administration of lipopolysaccharide (LPS) in rats (5). It is also to be noted that H 2 S is capable of activating TRPA1 channels in addition to Ca v 3.2 (22) and that peripheral H 2 S-induced mechanical hyperalgesia and allodynia require activation of both Ca v 3.2 and TRPA1 (23) (Fig.…”