The recent article by Pickert et al.1 regarding inhibition of GTP cyclohydrolase to attenuate tumor growth provided for very stimulating reading. Interestingly, recent data suggest that GTP cyclohydrolase 1 (GCH1) plays a significant role in modulating peripheral inflammatory as well as neuropathic pain. Thus, GCH1 may play a significant role in mitigating pain as well as tumor growth in cancer patients.
For instance, various polymorphisms of the GCH1 gene have been reported which significantly influence pain ratings in response to exogenous stimuli such as capsaicin.2 In fact, certain GCH1 haplotypes (rs8007267, rs10483639 and rs3783641) have been identified that are associated with lower opioid dose requirements as a result of lower 24 hour pain scores.3 As a result, in these haplotypes, there is decreased tetrahydrobiopterin (BH4) upregulation and attenuated GCH1 levels contributing to higher hypralgesia thresholds. In silico screening for the above three GCH1 genetic variants of the GCH1 gene helps in diagnosis of the pain-protective GCH1 haplotypes with 100% specificity as well as sensitivity.4 The population frequency of these pain protective haplotypes is 15.40%.
GCH1 levels can be modulated and altered in various ways. For instance, Kim et al.5 have recently reported the use of an adeno-associated virus encoding both a small hairpin RNA against GCH1 and a GFP reporter gene (rAAV-shGCH1) for reducing GCH1 expression in dorsal root ganglia in animal models. The inhibition of GCH1 also accentuates the analgesic properties of other agents such ass morphine. The added benefit is that there is no enhancement of the toxicity of the concurrently administered opioid. Diaminohydroxypyrimidine is another recently identified GCH1 inhibitor.6
Clearly, there is an urgent need to identify other inhibitors of GCH1 that may one day very well change the very face of pain management especially in cancer patients.