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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We acknowledge R. Keller, co-principal investigator of the Maine Lumbar Spine Study, for his support and advice; A. Häussler, P. Kahler, I.N. Grundei, A. Kirchhof, A. Bollettino, H. Hipp and C. McKnight for technical assistance; S. Niemann and A. Kingman for genetic and biostatistical advice; E.R. Werner for biochemical advice and C. Hesslinger (Pharmazentrum Frankfurt, J.W. Goethe-University, Frankfurt, Germany; current affiliation: ALTANA Pharma AG, Konstanz, Germany) for the GTP cyclohydrolase antibody. The work was supported by grants from the US National Institutes of Health (NS039518 and NS038253, C.J.W.; NS052623, M.C.; Z01 DE00366, M.B.M.; Z01 AA000301, D.G.; DE16558, DE07509 and NS045685, L.D. and W.M.), the Deutsche Forschungsgemeinschaft (DFG322_2-1, S.F.B.; 553/C6, I.T. and G.G.), the Bundesministerium für Bildung und Forschung (BMBF 01, E.M.; 0511, G.G.) and the Dr. Robert Pfleger Foundation (I.T.).
C.J.W. has an equity holding in a company, Solace Pharma Inc., that is negotiating to license technology from the Massachusetts General Hospital related to the manuscript. All other authors have no competing interests.
Analgesic effects of DAHP in neuropathic pain models. (PDF 387 kb)
DAHP is analgesic when delivered intrathecally but has no activity in the forced swim test. (PDF 400 kb)
Microarray expression profiles of BH4-related enzymes. (PDF 397 kb)
Haplotype block organization of GCH1. (PDF 1890 kb)
Demographic data of the Lumbar Root Pain study. (PDF 89 kb)
Locations and allelic frequencies of 15 GCH1 SNPs. (PDF 142 kb)
Primer and probe sequences for 5′ nuclease genotyping of 15 .GCH1 markers (PDF 132 kb)
Associations of experimental pain with the number of copies of the GCH1 pain-protective haplotype. (PDF 150 kb)
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Tegeder, I., Costigan, M., Griffin, R. et al. GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. Nat Med 12, 1269–1277 (2006) doi:10.1038/nm1490
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