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.