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Tegeder, I. et al. GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. Nature Med. 12, 1269-1277

Harvard University, Cambridge, Massachusetts, United States
Nature Medicine (Impact Factor: 28.05). 12/2006; 12(11):1269-77. DOI: 10.1038/nm1490
Source: PubMed

ABSTRACT We report that GTP cyclohydrolase (GCH1), the rate-limiting enzyme for tetrahydrobiopterin (BH4) synthesis, is a key modulator of peripheral neuropathic and inflammatory pain. BH4 is an essential cofactor for catecholamine, serotonin and nitric oxide production. After axonal injury, concentrations of BH4 rose in primary sensory neurons, owing to upregulation of GCH1. After peripheral inflammation, BH4 also increased in dorsal root ganglia (DRGs), owing to enhanced GCH1 enzyme activity. Inhibiting this de novo BH4 synthesis in rats attenuated neuropathic and inflammatory pain and prevented nerve injury-evoked excess nitric oxide production in the DRG, whereas administering BH4 intrathecally exacerbated pain. In humans, a haplotype of the GCH1 gene (population frequency 15.4%) was significantly associated with less pain following diskectomy for persistent radicular low back pain. Healthy individuals homozygous for this haplotype exhibited reduced experimental pain sensitivity, and forskolin-stimulated immortalized leukocytes from haplotype carriers upregulated GCH1 less than did controls. BH4 is therefore an intrinsic regulator of pain sensitivity and chronicity, and the GTP cyclohydrolase haplotype is a marker for these traits.

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    • "Nevertheless, the finding that spontaneous activity in hph-1 mice was not influenced in the second phase after injection of both low and high formalin concentrations suggests that at least in hph-1 mice, changes in GTP-CH1 activity is not critical for the processes driving the second phase of the formalin test. Tegeder et al., 2006 showed that peripheral inflammation increased the BH4 concentrations in DRG compared to that of naïve rats, and that administration of DAHP reduced this excess BH4 production [4]. Reductions in BH4 synthesis in hph-1 mice have been shown in several tissues, including brain, liver and lung [13] [26] [27], and GTP-CH1 activity is probably reduced in all tissues where it is normally expressed. "
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    ABSTRACT: Background GTP cyclohydrolase 1 (GTP-CH1), the rate-limiting enzyme in the synthesis of tetrahydrobiopterin (BH4), encoded by the GCH1 gene, has been implicated in the development and maintenance of inflammatory pain in rats. In humans, homozygous carriers of a “pain-protective” (PP) haplotype of the GCH1 gene have been identified exhibiting lower pain sensitivity, but only following pain sensitisation. Ex vivo, the PP GCH1 haplotype is associated with decreased induction of GCH1 after stimulation, whereas the baseline BH4 production is not affected. Contrary, loss of function mutations in the GCH1 gene results in decreased basal GCH1 expression, and is associated with DOPA-responsive dystonia (DRD). So far it is unknown if such mutations affect acute and inflammatory pain. Results In the current study, we examined the involvement of the GCH1 gene in pain models using the hyperphenylalaninemia 1 (hph-1) mouse, a genetic model for DRD, with only 10% basal GTP-CH1 activity compared to wild type mice. The study included assays for determination of acute nociception as well as models for pain after sensitisation. Pain behavioural analysis of the hph-1 mice showed reduced pain-like responses following intraplantar injection of CFA, formalin and capsaicin; whereas decreased basal level of GTP-CH1 activity had no influence in naïve hph-1 mice on acute mechanical and heat pain thresholds. Moreover, the hph-1 mice showed no signs of motor impairment or dystonia-like symptoms. Conclusions In this study, we demonstrate novel evidence that genetic mutations in the GCH1 gene modulate pain-like hypersensitivity. Together, the present data suggest that BH4 is not important for basal heat and mechanical pain, but they support the hypothesis that BH4 plays a role in inflammation-induced hypersensitivity. Our studies suggest that the BH4 pathway could be a therapeutic target for the treatment of inflammatory pain conditions. Moreover, the hph-1 mice provide a valid model to study the consequence of congenital deficiency of GCH1 in painful conditions.
    Molecular Pain 02/2013; 9(1):5. DOI:10.1186/1744-8069-9-5 · 3.53 Impact Factor
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    • "release depends on the cellular redox status and the amount and site of its production by nitric oxide synthases (NOS). Chemical inhibitors of NOS [4] [5] [6] [7] [8] or inhibitors of the NOScoenzyme , tetrahydrobiopterin [9] [10], or deletion of neuronal [11] or inducible NOS [12] all reduce neuropathic or inflammatory pain in rodents. This is partly due to a reduction of cGMP production and attenuation of protein kinase G activation [7] [8]. "
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    Journal of proteomics 05/2012; 75(13):3987-4004. DOI:10.1016/j.jprot.2012.05.006 · 3.93 Impact Factor
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    • "Data are adapted from Light et al. [89], White et al. [90], and unpublished observations. neuronal expression for genes linked to pain affect and mood [93] [94] [95], thus strengthening use of this approach in the context of FMS. In all studies of gene expression, there is also the additional limitation that this is an indication that processes have been engaged in an effort to increase or decrease the production of a specific receptor or other protein , and that changes in actual protein levels may not always occur. "
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    01/2012; 2012:427869. DOI:10.1155/2012/427869
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