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

Tsubota-Matsunami, Maho; Noguchi, Yukiko; Okawa, Yasumasa; Sekiguchi, Fumiko; Kawabata, Atsufumi

doi:10.1254/jphs.12086sc

Cited by 46 publications

(35 citation statements)

References 14 publications

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“…In contrast to the results obtained with intraplantar injections of NaHS, intracolonic administration of NaHS produced identical nociceptive effects in Trpa1 +/+ and Trpa1 −/− mice, suggesting that although TRPA1 stimulation is essential for the somatic pronociceptive effects of H 2 S, it is not required for the visceral effects of H 2 S. It is worth noting that administration of vehicle itself produced a significant nociceptive response, as reported by others [10], [29]. Previous studies have demonstrated a referred mechanical hyperalgesia following colonic instillation of NaHS in mice [10], [29]. Here, we found no difference between the sensitivity to abdominal stimulation with von Frey filaments between mice treated with vehicle and NaHS and the mechanical sensitivity was virtually identical in Trpa1 +/+ and Trpa1 −/− mice (Fig.…”

Section: Resultsmentioning

confidence: 53%

TRPA1 Has a Key Role in the Somatic Pro-Nociceptive Actions of Hydrogen Sulfide

2012

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Hydrogen sulfide (H2S), which is produced endogenously from L-cysteine, is an irritant with pro-nociceptive actions. We have used measurements of intracellular calcium concentration, electrophysiology and behavioral measurements to show that the somatic pronociceptive actions of H2S require TRPA1. A H2S donor, NaHS, activated TRPA1 expressed in CHO cells and stimulated DRG neurons isolated from Trpa1+/+ but not Trpa1−/− mice. TRPA1 activation by NaHS was pH dependent with increased activity at acidic pH. The midpoint of the relationship between NaHS EC50 values and external pH was pH 7.21, close to the expected dissociation constant for H2S (pKa 7.04). NaHS evoked single channel currents in inside-out and cell-attached membrane patches consistent with an intracellular site of action. In behavioral experiments, intraplantar administration of NaHS and L-cysteine evoked mechanical and cold hypersensitivities in Trpa1+/+ but not in Trpa1−/− mice. The sensitizing effects of L-cysteine in wild-type mice were inhibited by a cystathionine β-synthase inhibitor, D,L-propargylglycine (PAG), which inhibits H2S formation. Mechanical hypersensitivity evoked by intraplantar injections of LPS was prevented by PAG and the TRPA1 antagonist AP-18 and was absent in Trpa1−/− mice, indicating that H2S mediated stimulation of TRPA1 is necessary for the local pronociceptive effects of LPS. The pro-nociceptive effects of intraplantar NaHS were retained in Trpv1−/− mice ruling out TRPV1 as a molecular target. In behavioral studies, NaHS mediated sensitization was also inhibited by a T-type calcium channel inhibitor, mibefradil. In contrast to the effects of NaHS on somatic sensitivity, intracolonic NaHS administration evoked similar nociceptive effects in Trpa1+/+ and Trpa1−/− mice, suggesting that the visceral pro-nociceptive effects of H2S are independent of TRPA1. In electrophysiological studies, the depolarizing actions of H2S on isolated DRG neurons were inhibited by AP-18, but not by mibefradil indicating that the primary excitatory effect of H2S on DRG neurons is TRPA1 mediated depolarization.

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Section: Resultsmentioning

confidence: 53%

TRPA1 Has a Key Role in the Somatic Pro-Nociceptive Actions of Hydrogen Sulfide

2012

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“…10] and genetic silencing of TRPA1 (Okubo et al, 2012). The role of TRPA1 in H 2 S-induced visceral pain, however, remains controversial, with one group finding similar pain behavior in wild-type and Trpa1 knockout mice and another group reporting the involvement of both TRPA1 and Ca v 3.2 channels in H 2 S-induced colonic pain and referred hyperalgesia (Tsubota-Matsunami et al, 2012).…”

Section: Transient Receptor Potential Channels: Acquired Diseasesmentioning

confidence: 99%

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

2014

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“…TRPA1 receptors are partially responsible for mechanosensitive responses of afferent neurons in mouse colon (12,13). Recent evidence suggests that H 2 S acts on TRPA1 directly in colonic afferent neurons to enhance nociceptive function (110).…”

Section: Lindenmentioning

confidence: 99%

Hydrogen Sulfide Signaling in the Gastrointestinal Tract

Linden

2014

Antioxidants & Redox Signaling

194

112

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Significance: The current literature regarding the effects of the gaseous signal molecule hydrogen sulfide (H 2 S) in the gastrointestinal system is reviewed. Bacterial, host and pharmaceutical-derived H 2 S are all considered and presented according to the physiological or pathophysiological effects of the gaseous signal molecule. These subjects include the toxicology of intestinal H 2 S with emphasis on bacterial-derived H 2 S, especially from sulfatereducing bacteria, the role of endogenous and exogenous H 2 S in intestinal inflammation, and the roles of H 2 S in gastrointestinal motility, secretion and nociception. Recent Advances: While its pro-and anti-inflammatory, smooth muscle relaxant, prosecretory, and pro-and antinociceptive actions continue to remain the major effects of H 2 S in this system; recent findings have expanded the potential molecular targets for H 2 S in the gastrointestinal tract. Critical Issues: Numerous discrepancies remain in the literature, and definitive molecular targets in this system have not been supported by the use of competitive antagonism. Future Directions: Future work will hopefully resolve discrepancies in the literature and identify molecular targets and mechanisms of action for H 2 S. It is clear from the current literature that the long-appreciated relationship between H 2 S and the gastrointestinal tract continues to be strong as we endeavor to unravel its mysteries. Antioxid. Redox Signal. 20, 818-830.

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

Cited by 46 publications

References 14 publications

TRPA1 Has a Key Role in the Somatic Pro-Nociceptive Actions of Hydrogen Sulfide

TRPA1 Has a Key Role in the Somatic Pro-Nociceptive Actions of Hydrogen Sulfide

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

Hydrogen Sulfide Signaling in the Gastrointestinal Tract

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