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Updated: Apr 16, 2026

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Published on: May 16, 2022
Evidence of a role for GTP cyclohydrolase-1 in visceral pain
D C Bulmer1, C A Botha, A Wheeldon
1Wingate 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.
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.
Key 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 & Inferences:
The data generated indicate that GCH-1 plays a role in visceral pain processing that requires more detailed investigation.
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