title: Evidence of a role for GTP cyclohydrolase-1 in visceral pain.
abstract: BACKGROUND
  The enzyme guanosine triphosphate-cyclohydrolase-1 (GCH-1) is a rate limiting step in the de novo synthesis of tetrahydrobiopterin (BH4) a co-factor in monoamine synthesis and nitric oxide production. GCH-1 is strongly implicated in chronic pain based on data generated using the selective GCH-1 inhibitor 2,4-diamino-6-hydroxypyrimidine (DAHP), and studies which have identified a pain protective GCH-1 haplotype associated with lower BH4 production and reduced pain.
  
  
  METHODS
  To investigate the role for GCH-1 in visceral pain we examined the effects of DAHP on pain behaviors elicited by colorectal injection of mustard oil in rats, and the pain protective GCH-1 haplotype in healthy volunteers characterized by esophageal pain sensitivity before and after acid injury, and assessed using depression and anxiety questionnaires.
  
  
  RESULTS
  In rodents pretreatment with DAHP produced a substantial dose related inhibition of pain behaviors from 10 to 180 mg/kg i.p. (p < 0.01 to 0.001). In healthy volunteers, no association was seen between the pain protective GCH-1 haplotype and the development of hypersensitivity following injury. However, a substantial increase in baseline pain thresholds was seen between first and second visits (26.6 ± 6.2 mA) in subjects who sensitized to esophageal injury and possessed the pain protective GCH-1 haplotype compared with all other groups (p < 0.05). Furthermore the same subjects who sensitized to acid and possessed the haplotype, also had significantly lower depression scores (p < 0.05).
  
  
  CONCLUSIONS
  The data generated indicate that GCH-1 plays a role in visceral pain processing that requires more detailed investigation.
authors.affiliation: Wingate Institute of Neurogastroenterology, Blizard Institute, Bart's and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK; National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Bart's and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK; GlaxoSmithKline Research & Development, Medicines Research Centre, Hertfordshire, UK.
authors.forename: D C
authors.initials: DC
authors.lastname: Bulmer
authors.forename: C A
authors.initials: CA
authors.lastname: Botha
authors.forename: A
authors.initials: A
authors.lastname: Wheeldon
authors.forename: K
authors.initials: K
authors.lastname: Grey
authors.forename: C A
authors.initials: CA
authors.lastname: Mein
authors.forename: K
authors.initials: K
authors.lastname: Lee
authors.forename: C H
authors.initials: CH
authors.lastname: Knowles
authors.forename: W J
authors.initials: WJ
authors.lastname: Winchester
authors.forename: Q
authors.initials: Q
authors.lastname: Aziz
mesh_terms: D000328:Adult; D000818:Animals; D001007:Anxiety / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects*; D003106:Colon; D018592:Cross-Over Studies; D003863:Depression / Q000523:psychology; D004558:Electric Stimulation; D004947:Esophagus / Q000187:drug effects; D005260:Female; D006136:GTP Cyclohydrolase / Q000037:antagonists & inhibitors* / Q000235:genetics; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D006851:Hydrochloric Acid / Q000009:adverse effects; D007042:Hypoxanthines / Q000494:pharmacology; D008297:Male; D009149:Mustard Plant / Q000009:adverse effects; D010641:Phenotype; D010938:Plant Oils / Q000009:adverse effects; D065840:Protective Factors; D051381:Rats; D012007:Rectum; D059265:Visceral Pain / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000523:psychology
chemical_list: D007042:Hypoxanthines; D010938:Plant Oils; D006136:GTP Cyclohydrolase; C017202:2,4-diaminohypoxanthine; D006851:Hydrochloric Acid; C027793:mustard oil
keywords: GCH-1; GTP-cyclohydrolase-1; esophageal pain; inflammation; pain genes; visceral pain