Skip to main content

GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence.

Publication ,  Journal Article
Tegeder, I; Costigan, M; Griffin, RS; Abele, A; Belfer, I; Schmidt, H; Ehnert, C; Nejim, J; Marian, C; Scholz, J; Wu, T; Allchorne, A ...
Published in: Nat Med
November 2006

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Nat Med

DOI

ISSN

1078-8956

Publication Date

November 2006

Volume

12

Issue

11

Start / End Page

1269 / 1277

Location

United States

Related Subject Headings

  • Rats
  • Prospective Studies
  • Pain Threshold
  • Pain Management
  • Pain
  • Immunology
  • Humans
  • Haplotypes
  • GTP Cyclohydrolase
  • Enzyme Inhibitors
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Tegeder, I., Costigan, M., Griffin, R. S., Abele, A., Belfer, I., Schmidt, H., … Woolf, C. J. (2006). GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. Nat Med, 12(11), 1269–1277. https://doi.org/10.1038/nm1490
Tegeder, Irmgard, Michael Costigan, Robert S. Griffin, Andrea Abele, Inna Belfer, Helmut Schmidt, Corina Ehnert, et al. “GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence.Nat Med 12, no. 11 (November 2006): 1269–77. https://doi.org/10.1038/nm1490.
Tegeder I, Costigan M, Griffin RS, Abele A, Belfer I, Schmidt H, et al. GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. Nat Med. 2006 Nov;12(11):1269–77.
Tegeder, Irmgard, et al. “GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence.Nat Med, vol. 12, no. 11, Nov. 2006, pp. 1269–77. Pubmed, doi:10.1038/nm1490.
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. GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. Nat Med. 2006 Nov;12(11):1269–1277.

Published In

Nat Med

DOI

ISSN

1078-8956

Publication Date

November 2006

Volume

12

Issue

11

Start / End Page

1269 / 1277

Location

United States

Related Subject Headings

  • Rats
  • Prospective Studies
  • Pain Threshold
  • Pain Management
  • Pain
  • Immunology
  • Humans
  • Haplotypes
  • GTP Cyclohydrolase
  • Enzyme Inhibitors