Hydrogen sulfide downregulates colonic afferent sensitivity by a nitric oxide synthase-dependent mechanism in mice

The effect of hydrogen sulfide (H₂ S) on visceral nociception is elusive. The conflicting evidence of its pro- and antinociceptive effects raises a series of questions with respect to the effect of H₂ S on colonic afferent activity and the underlying mechanism, which was further elucidated in this study.

Colonic mesenteric afferent nerve spikes of normal male C57BL/6J mice, Cbs^+/- mice, and Wistar rats were recorded in vitro. The abdominal withdrawal reflex (AWR) induced by colorectal distension (CRD) was evaluated in Cbs^+/- mice and WT littermates.

Sodium hydrosulfide (NaHS) significantly decreased colonic afferent spontaneous discharge, chemosensitivity to bradykinin, mechanosensitivity to ramp distention, and intraluminal pressure in mice. Reducing the relaxant action of NaHS on intestinal smooth muscle using the nonspecific K⁺ channel blocker TEA (10 mmol/L) did not block the inhibition of NaHS on afferent nerve activity. The inhibitory effects of NaHS (0.5 mmol/L) on colonic afferent sensitivity were largely eliminated by the pretreatment with nonspecific NOS inhibitor N^G -Methyl-l-arginine acetate salt (1 mmol/L), the specific nNOS inhibitor NPLA (1 μmol/L), or N-type Ca²⁺ channel blocker ω-conotoxin GVIA (1 μmol/L). Compared with WT mice, Cbs^+/- mice showed increased mesenteric afferent sensitivity to colonic distention and enhanced hyperalgesic response to CRD. Intraperitoneal administration of NaHS (60 μmol/kg) alleviated the nociception response to CRD in both Cbs^+/- and WT mice.

H₂ S downregulates colonic mesenteric afferent sensitivity by a nNOS-dependent mechanism in mice. Our findings may demonstrate a new mechanism for the antinociceptive effect of H₂ S in colon.