title: Upregulation of cystathionine β-synthetase expression contributes to visceral hyperalgesia induced by heterotypic intermittent stress in rats.
abstract: BACKGROUND
  Hydrogen sulfide (H₂S) functions as a neuromodulator, but whether it modulates visceral pain is not well known. This study was designed to determine the role for the endogenous H₂S producing enzyme cystathionine β-synthetase (CBS) and cystathionine γ-lyase (CSE) in a validated rat model of visceral hyperalgesia (VH).
  
  
  METHODS
  VH was induced by nine-day heterotypic intermittent stress (HIS). Abdominal withdrawal reflex (AWR) scores were determined by measuring the visceromoter responses to colorectal distension (CRD). Dorsal root ganglia (DRG) neurons innervating the colon were labeled by injection of DiI (1,1'-dioleyl-3,3,3',3-tetramethylindocarbocyanine methanesulfonate) into the colon wall. Patch clamp recording techniques were employed to examine excitability and sodium channel currents of colon specific DRG neurons. Tissues from colon related thoracolumbar DRGs were analyzed for CBS, CSE and sodium channel expression.
  
  
  RESULTS
  HIS significantly increased the visceromotor responses to CRD in association with an upregulated expression of CBS not CSE proteins in colon related DRGs. Administration of O-(Carboxymethyl)hydroxylamine hemihydrochloride (AOAA), an inhibitor of CBS, attenuated the AWR scores in HIS-treated rats, in a dose dependent fashion. In contrast, AOAA did not produce any effect on AWR scores in healthy control rats. AOAA reversed the potentiation of sodium channel current densities of colon specific DRG neurons of HIS rats. To further confirm the role for CBS-H₂S signaling, NaHS was used to mimic the production of H₂S by CBS. Application of NaHS significantly enhanced neuronal excitability and potentiated sodium channel current densities of colon DRG neurons from healthy control rats. Furthermore, AOAA reversed the upregulation of Na(V)1.7 and Na(V)1.8 in colon related DRGs of HIS rats.
  
  
  CONCLUSIONS
  Our results suggest that upregulation of CBS expression might play an important role in developing VH via sensitization of sodium channels in peripheral nociceptors, thus identifying a specific neurobiological target for the treatment of VH in functional bowel syndromes.
authors.affiliation: Institute of Neuroscience, Key Laboratory of Pain Basic Research and Clinic Therapy, Department of Neurobiology, Soochow University, Suzhou, P. R. China.
authors.forename: Yongmeng
authors.initials: Y
authors.lastname: Wang
authors.forename: Ruobing
authors.initials: R
authors.lastname: Qu
authors.forename: Shufen
authors.initials: S
authors.lastname: Hu
authors.forename: Ying
authors.initials: Y
authors.lastname: Xiao
authors.forename: Xinghong
authors.initials: X
authors.lastname: Jiang
authors.forename: Guang-Yin
authors.initials: GY
authors.lastname: Xu
mesh_terms: D000818:Animals; D003541:Cystathionine beta-Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006862:Hydrogen Sulfide / Q000009:adverse effects / Q000378:metabolism; D006930:Hyperalgesia / Q000201:enzymology* / Q000235:genetics; D007410:Intestinal Diseases / Q000201:enzymology / Q000209:etiology / Q000235:genetics; D008297:Male; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D012020:Reflex, Abdominal / Q000187:drug effects; D013315:Stress, Psychological / Q000235:genetics / Q000503:physiopathology*; D013440:Sulfides / Q000494:pharmacology; D016559:Tacrolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D015854:Up-Regulation / Q000502:physiology; D014781:Viscera / Q000378:metabolism / Q000473:pathology; D059265:Visceral Pain / Q000201:enzymology* / Q000209:etiology
chemical_list: C112418:32-ascomycinyloxyacetic acid; D004791:Enzyme Inhibitors; D013440:Sulfides; D003541:Cystathionine beta-Synthase; C025451:sodium bisulfide; D016559:Tacrolimus; D006862:Hydrogen Sulfide