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

Abstract

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 Cav3.2 isoform of T-type Ca2+ 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 Ca2+ channel inhibitor, and also suppressed by pretreatment with i.t. and i.pl. zinc chloride, known to preferentially inhibit Cav3.2 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 Cav3.2 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 Cav3.2 T-type Ca2+ channels expressed in the primary afferents and/or spinal nociceptive neurons, leading to sensitization of nociceptive processing and hyperalgesia.

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].…”

BK Channels – Focus on Polyamines, Ethanol/Acetaldehyde and Hydrogen Sulfide (H2S)

“…In peripheral tissue, however, H 2 S reduces T-type Ca 2+ channel activity leading to hyperalgesia . T-type calcium channels are also involved in pain processing of spinal nociceptive neurons (Maeda et al, 2009), in colon ) and in pancreas (Nishimura et al, 2009). H 2 S decreased the mechanical contraction of rat cardiomyocytes through inhibition of L-type calcium channels (Sun et al, 2008).…”

Estudo dos efeitos do composto GYY-4137, um doador de sulfeto de hidrogênio (H₂S), na sinovite aguda induzida por carragenina na articulação temporomandibular de ratos.

“…Tem efeito pró-nociceptivo quando administrado por via intratecal (Maeda et al, 2009), intraplantar (Kawabata et al, 2007 ou intracolônica Por outro lado, as propriedades anti-inflamatórias do H 2 S têm sido observadas em diversos modelos experimentais, tais como o de edema de pata induzido por CGN (Zanardo et al, 2006), artrite (Ekundi-Valentim et al, 2010;Li et al, 2013), lesão pulmonar (Esechie et al, 2008), asma (Benetti et al, 2013) e em modelo de dor viceral induzida por distensão coloretal (Distrutti et al, 2010).…”

“…Enquanto a liberação de H 2 S a partir do NaHS é espontânea e rápida, a liberação de H 2 S pelo composto GYY-4137 ocorre de forma lenta (e assim durante longos períodos de tempo), possivelmente mimetizando a cinética de produção endógena do H 2 S (Whiteman et al, 2010 (Cunha et al, 2008;Donatti et al, 2014;Zanardo et al, 2006). Os canais de Ca 2+ tipo T, por sua vez, são geralmente relacionados com os efeitos pró-inflamatórios e pró-nociceptivos deste mediador (Maeda et al, 2009;Schemann, Grundy, 2009 (Streng et al, 2008;Sun et al, 2008;Telezhkin et al, 2009;Trevisani et al, 2005).…”