The endogenous hydrogen sulfide producing enzyme cystathionine-beta synthase contributes to visceral hypersensitivity in a rat model of irritable bowel syndrome.
BACKGROUND
The pathogenesis of visceral hypersensitivity, a characteristic pathophysiological feature of irritable bowel syndrome (IBS), remains elusive. Recent studies suggest a role for hydrogen sulfide (H2S) in pain signaling but this has not been well studied in visceral models of hyperalgesia. We therefore determined the role for the endogenous H2S producing enzyme cystathionine-beta-synthetase (CBS) in a validated rat model of IBS-like chronic visceral hyperalgesia (CVH). CVH was induced by colonic injection of 0.5% acetic acid (AA) in 10-day-old rats and experiments were performed at 8-10 weeks of age. Dorsal root ganglion (DRG) neurons innervating the colon were labeled by injection of DiI (1,1'-dioleyl-3,3,3',3-tetramethylindocarbocyanine methanesulfonate) into the colon wall.


RESULTS
In rat DRG, CBS-immunoreactivity was observed in approximately 85% of predominantly small- and medium-sized neurons. Colon specific DRG neurons revealed by retrograde labeling DiI were all CBS-positive. CBS-positive colon neurons co-expressed TRPV1 or P2X3 receptors. Western blotting analysis showed that CBS expression was significantly increased in colon DRGs 8 weeks after neonatal AA-treatment. Furthermore, the CBS inhibitor hydroxylamine markedly attenuated the abdominal withdrawal reflex scores in response to colorectal distention in rats with CVH. By contrast, the H2S donor NaHS significantly enhanced the frequency of action potentials of colon specific DRG neurons evoked by 2 times rheobase electrical stimulation.


CONCLUSIONS
Our results suggest that upregulation of CBS expression in colonic DRG neurons and H2S signaling may play an important role in developing CVH, thus identifying a specific neurobiological target for the treatment of CVH in functional bowel syndromes.
Xu
Guang-Yin
GY
Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555-0655, USA. gyxu@utmb.edu
Winston
John H
JH
Shenoy
Mohan
M
Zhou
Shufang
S
Chen
Jiande D Z
JD
Pasricha
Pankaj J
PJ
D019342:Acetic Acid / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D003106:Colon / Q000294:innervation / Q000378:metabolism* / Q000473:pathology; D003541:Cystathionine beta-Synthase / Q000378:metabolism / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D005727:Ganglia, Spinal / Q000378:metabolism* / Q000473:pathology; D006862:Hydrogen Sulfide / Q000378:metabolism*; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism*; D043183:Irritable Bowel Syndrome / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D012020:Reflex, Abdominal; D014781:Viscera / Q000294:innervation / Q000378:metabolism / Q000473:pathology
D003541:Cystathionine beta-Synthase; D019342:Acetic Acid; D006862:Hydrogen Sulfide