GCH1 variants, tetrahydrobiopterin and their effects on pain sensitivity

Abstract

Background A great proportion of the variation in pain experience and chronicity is caused by heritable factors. Within the last decades several candidate genes have been discovered either increasing or decreasing pain sensitivity or the risk of chronic pain in humans. One of the most studied genes is the GCH1 gene coding for the enzyme GTP cyclohydrolase 1 (GCH1). GCH1 catalyses the initial and rate-limiting step in the biosynthesis of tetrahydrobiopterin (BH4). The main function of BH4 is regulation of monoamine and nitric oxide biosynthesis, all involved in nociceptive signalling. Methods In this topical review we focus on the implication of the GCH1 gene and BH4 in painful conditions. We discuss experimental evidence from our group in relation to relevant research publications evaluating the BH4 pathway in pain. Studies assessing the role of GCH1 and BH4 in pain consist of human and animal studies, including DOPA-responsive dystonia (DRD) patients and hph-1 mice (a genetic mouse model of DRD) having mutations in the GCH1 gene as well as preclinical studies with the GCH1 inhibitor 2,4-diamino-6-hydroxypyrimidine (DAHP). The hypothesis is that genetic and pharmacological reduction of GCH1 would result in lower pain sensitivity. Results Previous studies have demonstrated that a particular "pain protective" GCH1 haplotype, found in 15% of the general human population, is linked to decreased pain sensitivity. We further support these findings in DRD patients, showing normal thresholds to mechanical and thermal stimuli, whereas a trend towards lower pain sensitivity is seen following chemical pain sensitisation. Consistent with these observations, non-injured hph-1 mice displayed normal mechano- and thermosensation compared to wild-type mice. After peripheral inflammation with Complete Freund' Adjuvant or sensitisation with capsaicin the mutant mice exhibited lower sensitivity to mechanical and heat stimuli. Moreover, hph-1 mice showed decreased nociception in the first phase of the formalin test. Several studies report analgesic effects of GCH1 inhibition with 90-270 mg/kg DAHP in rat models of inflammatory and neuropathic pain. However, we could not completely replicate these findings in mice. Fairly higher doses of DAHP (≥270 mg/kg) were needed to reduce inflammatory pain in mice, but the window between antinociception and toxic effects was small, since 400 mg/kg DAHP affected motor performance and general appearance. Also, the analgesic effects were marginal in mice compared to that observed in rats. Conclusions Variations in the GCH1 gene in both humans and mice appear to regulate pain sensitivity and pain behaviours, particularly after pain sensitisation, whereas pain sensitivity to phasic mechanical and thermal stimuli is normal. Moreover, pharmacological inhibition of GCH1 shows antinociceptive effects in preclinical pain studies, though our studies imply that GCH1 inhibition may have a small therapeutic index. Implications The implication of the GCH1 gene in pain may increase our understanding of the risk ...

Intraplantar injection of tetrahydrobiopterin induces nociception in mice

“…the nociceptive system [2]. Here, we aimed to examine the mechanism(s) behind the acute BH4-evoked nociception in mice.…”

“…BH4 is therefore crucial for the biosynthesis of catecholamines, serotonin and nitric oxide (NO) [1,2]. Given the pleiotropic biochemical properties of BH4, it is implicated in a number of pathological conditions, such as cardiovascular diseases, neurological diseases and psychiatric disorders [1,3] pathway has also been recognised as a potential, new target for the development of novel analgesics [2,4]. This was triggered by findings that demonstrated a link between BH4 biosynthesis and pain persistence in humans and rodents [5,6].…”

“…The biosynthesis of BH4 is highly controlled by the de novo synthetic pathway; the salvage pathway and the recycling pathway [1,2]. Biosynthesis of BH4 proceeds from GTP via three reactions catalysed by guanosine triphosphate cyclohydrolase 1,6-pyruvoyltetrahydrobiopterin synthase and sepiapterin reductase.…”

“…Biosynthesis of BH4 proceeds from GTP via three reactions catalysed by guanosine triphosphate cyclohydrolase 1,6-pyruvoyltetrahydrobiopterin synthase and sepiapterin reductase. Under normal conditions, sensory neuron activity of the synthetic pathway is low and the salvage and recycling pathways preserve BH4 homeostasis [2]. However, after peripheral injury or inflammation, guanosine triphosphate cyclohydrolase 1 activity markedly increases in sensory neurons accompanied by increased BH4 biosynthesis [5].…”

Association of rs3783641 single‐nucleotide polymorphism in GTP cyclohydrolase 1 gene with post‐herpetic neuralgia

“…Understanding genetic contribution to individual differences in pain sensitivity could have substantial implications for predicting pain sensitivity and modulating pain therapy. A number of pre‐clinical studies have demonstrated that inhibition of enzymes involved in the biosynthetic pathway of BH4 produces analgesic effects in different animal models of pain . Early research revealed the potential predictive value of GCH1 genotyping in terms of clinical outcome following surgical treatment for degenerative disc disease (DDD) .…”