Hydrogen sulfide‐induced mechanical hyperalgesia and allodynia require activation of both Ca_v3.2 and TRPA1 channels in mice

Abstract

Keywordstransient receptor potential ankyrin-1 (TRPA1); Cav3.2; T-type calcium channel; hydrogen sulfide; pain; hyperalgesia; allodynia BACKGROUND AND PURPOSEHydrogen sulfide, a gasotransmitter, facilitates somatic pain signals via activation of Cav3.2 T-type calcium channels in rats. Given evidence for the activation of transient receptor potential ankyrin-1 (TRPA1) channels by H2S, we asked whether TRPA1 channels, in addition to Cav3.2 channels, contribute to the H2S-induced mechanical hyperalgesia and allodynia in mice. EXPERIMENTAL APPROACHMechanical hyperalgesia and allodynia were evaluated by the von Frey test in mice. Cav3.2 or TRPA1 channels in the sensory neurons were silenced by repeated intrathecal administration of antisense oligodeoxynucleotides in mice. KEY RESULTSIntraplantar administration of NaHS evoked hyperalgesia and allodynia in mice, an effect attenuated or abolished by NNC 55-0396 or mibefradil, T-type calcium channel blockers, and by ascorbic acid or zinc chloride, known to selectively inhibit Cav3.2 channels, out of the three isoforms of T-type calcium channels. Silencing of Cav3.2 channels in the sensory neurons also prevented the NaHS-induced hyperalgesia and allodynia in mice. The NaHS-induced hyperalgesia and allodynia in mice were significantly suppressed by AP18, a TRPA1 channel blocker, and by silencing of TRPA1 channels in the sensory neurons. CONCLUSIONS AND IMPLICATIONSMechanical hyperalgesia and allodynia induced by NaHS/H2S required activation of both Cav3.2 and TRPA1 channels in mice.

Colonic Hydrogen Sulfide^|^ndash;Induced Visceral Pain and Referred Hyperalgesia Involve Activation of Both Cav3.2 and TRPA1 Channels in Mice

“…Our algesia in rats (2) and mice (8,9). These findings are in agreement with the recent evidence that Ca v 3.2, among the three isoforms of T-type Ca 2+ channels, in the sensory neurons plays a major role in processing of somatic (11) and visceral pain (12).…”

“…On the other hand, TRPA1 is now considered a target for H 2 S (8). Our latest study has shown that the activation of TRPA1 in addition to Ca v 3.2 is required for the H 2 Sinduced somatic pain (9). Similarly, the present findings suggest that the H 2 S-induced colonic pain and referred hyperalgesia are also dependent on activation of TRPA1.…”

“…It has also yet to be tested if the Ca v 3.2 isoform is involved in the H 2 S-induced visceral pain, as in the somatic pain signaling (2). Further, the TRPA1 channel, another target for H 2 S (8), in addition to Ca v 3.2, contributes to the H 2 S-induced somatic hyperalgesia/allodynia in mice (9), whereas the role of TRPA1 in the H 2 S-evoked visceral pain is still open to question. To address those remaining concerns and questions, here we further analyzed the mechanisms for the colonic pain / referred hyperalgesia caused by intracolonic administration of NaHS, a donor of H 2 S, in mice, using NNC 55-0396, a highly selective T-type Ca 2+ -channel blocker, the antisense (AS) oligodeoxynucleotides (ODNs) for silencing of Ca v 3.2, and AP18, a TRPA1 blocker.…”

“…repeatedly, once a day for 3 days in mice. Successful silencing of Ca v 3.2 by the AS-ODNs was determined by western blotting of Ca v 3.2 protein in the dorsal root ganglion (DRG) at L1 -L6 levels, as reported previously (9). Data are represented as means with S.E.M.…”

“…AITC was dissolved in peanut oil. (8,9). A mixture of two types of AS-ODNs for Ca v 3.2 or SC-ODN (No.…”