GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence

Irmgard Tegeder; Michael Costigan; Robert S. Griffin; Andrea Abele; Inna Belfer; Helmut Schmidt; Corina Ehnert; Jemiel Nejim; Claudiu Marian; Joachim Scholz; Tianxia Wu; Andrew Allchorne; Luda Diatchenko; Alexander M. Binshtok; David Goldman; Jan Adolph; Swetha Sama; Steven J. Atlas; William A. Carlezon; Aram Parsegian; Jörn Lötsch; Roger B. Fillingim; William Maixner; Gerd Geisslinger; Mitchell B. Max; Clifford J. Woolf

doi:10.1038/nm1490

GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence

Irmgard Tegeder, Michael Costigan, Robert S. Griffin, Andrea Abele, Inna Belfer, Helmut Schmidt, Corina Ehnert, Jemiel Nejim, Claudiu Marian, Joachim Scholz, Tianxia Wu, Andrew Allchorne, Luda Diatchenko, Alexander M. Binshtok, David Goldman, Jan Adolph, Swetha Sama, Steven J. Atlas, William A. Carlezon, Aram ParsegianJörn Lötsch, Roger B. Fillingim, William Maixner, Gerd Geisslinger, Mitchell B. Max, Clifford J. Woolf^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

500 Scopus citations

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.

Original language	English
Pages (from-to)	1269-1277
Number of pages	9
Journal	Nature Medicine
Volume	12
Issue number	11
DOIs	https://doi.org/10.1038/nm1490
State	Published - Nov 2006
Externally published	Yes

Bibliographical note

Funding Information:
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.).

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Tegeder, I., Costigan, M., Griffin, R. S., Abele, A., Belfer, I., Schmidt, H., Ehnert, C., Nejim, J., Marian, C., Scholz, J., Wu, T., Allchorne, A., Diatchenko, L., Binshtok, A. M., Goldman, D., Adolph, J., Sama, S., Atlas, S. J., Carlezon, W. A., ... Woolf, C. J. (2006). GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. Nature Medicine, 12(11), 1269-1277. https://doi.org/10.1038/nm1490

@article{83e658bfa7764e2682e45dbc4f6fd304,

title = "GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence",

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.",

author = "Irmgard Tegeder and Michael Costigan and Griffin, {Robert S.} and Andrea Abele and Inna Belfer and Helmut Schmidt and Corina Ehnert and Jemiel Nejim and Claudiu Marian and Joachim Scholz and Tianxia Wu and Andrew Allchorne and Luda Diatchenko and Binshtok, {Alexander M.} and David Goldman and Jan Adolph and Swetha Sama and Atlas, {Steven J.} and Carlezon, {William A.} and Aram Parsegian and J{\"o}rn L{\"o}tsch and Fillingim, {Roger B.} and William Maixner and Gerd Geisslinger and Max, {Mitchell B.} and Woolf, {Clifford J.}",

note = "Funding Information: We acknowledge R. Keller, co-principal investigator of the Maine Lumbar Spine Study, for his support and advice; A. H{\"a}ussler, 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 f{\"u}r Bildung und Forschung (BMBF 01, E.M.; 0511, G.G.) and the Dr. Robert Pfleger Foundation (I.T.).",

year = "2006",

month = nov,

doi = "10.1038/nm1490",

language = "אנגלית",

volume = "12",

pages = "1269--1277",

journal = "Nature Medicine",

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Tegeder, I, Costigan, M, Griffin, RS, Abele, A, Belfer, I, Schmidt, H, Ehnert, C, Nejim, J, Marian, C, Scholz, J, Wu, T, Allchorne, A, Diatchenko, L, Binshtok, AM, Goldman, D, Adolph, J, Sama, S, Atlas, SJ, Carlezon, WA, Parsegian, A, Lötsch, J, Fillingim, RB, Maixner, W, Geisslinger, G, Max, MB & Woolf, CJ 2006, 'GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence', Nature Medicine, vol. 12, no. 11, pp. 1269-1277. https://doi.org/10.1038/nm1490

TY - JOUR

T1 - GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence

AU - Tegeder, Irmgard

AU - Costigan, Michael

AU - Griffin, Robert S.

AU - Abele, Andrea

AU - Belfer, Inna

AU - Schmidt, Helmut

AU - Ehnert, Corina

AU - Nejim, Jemiel

AU - Marian, Claudiu

AU - Scholz, Joachim

AU - Wu, Tianxia

AU - Allchorne, Andrew

AU - Diatchenko, Luda

AU - Binshtok, Alexander M.

AU - Goldman, David

AU - Adolph, Jan

AU - Sama, Swetha

AU - Atlas, Steven J.

AU - Carlezon, William A.

AU - Parsegian, Aram

AU - Lötsch, Jörn

AU - Fillingim, Roger B.

AU - Maixner, William

AU - Geisslinger, Gerd

AU - Max, Mitchell B.

AU - Woolf, Clifford J.

N1 - Funding Information: 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.).

PY - 2006/11

Y1 - 2006/11

N2 - 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.

AB - 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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SP - 1269

EP - 1277

JO - Nature Medicine

JF - Nature Medicine

IS - 11

ER -

GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence

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