Nature Medicine
- 12, 1269 - 1277 (2006)
Published online: 22 October 2006; | doi:10.1038/nm1490
GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistenceIrmgard Tegeder1, 2, 10, Michael Costigan1, 10, Robert S Griffin1, Andrea Abele2, Inna Belfer3, 4, Helmut Schmidt2, Corina Ehnert2, Jemiel Nejim4, 9, Claudiu Marian2, Joachim Scholz1, Tianxia Wu4, Andrew Allchorne1, Luda Diatchenko5, Alexander M Binshtok1, David Goldman3, Jan Adolph2, Swetha Sama5, Steven J Atlas7, William A Carlezon8, Aram Parsegian8, Jörn Lötsch2, Roger B Fillingim6, William Maixner5, Gerd Geisslinger2, Mitchell B Max4 & Clifford J Woolf11
Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital & Harvard Medical School, 149 13th Street, Room 4309, Charlestown, Massachusetts 02129, USA. 2
Pharmazentrum Frankfurt, Institut für Klinische Pharmakologie / Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit, Klinikum der Johann Wolfgang Goethe-Universität, Theodor Stern Kai 7, Frankfurt am Main, 60590, Germany. 3
Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services, 5625 Fishers Lane, Room 3S-32, Rockville, Maryland 20852, USA. 4
National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, 10 Center Drive, Building 10, Room 3C-405, Bethesda, Maryland 20892, USA. 5
Center for Neurosensory Disorders, School of Dentistry, 2110 Old Dental Building, CB# 7455 University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7455, USA. 6
University of Florida College of Dentistry, Community Dentistry and Behavioral Science, 1329 SW 16th Street, Gainesville, Florida 32608, USA. 7
General Medicine Division and the Clinical Epidemiology Unit, Massachusetts General Hospital & Harvard Medical School, 15 Parkman Street, WAC 615, Boston, Massachusetts 02114, USA. 8
Department of Psychiatry, Harvard Medical School, McLean Hospital, 115 Mill Street, Belmont, Massachusetts 02478, USA. 9
Howard Hughes Medical Institute–National Institutes of Health Research Scholars Program, 1 Cloister Court, Building 60, Bethesda, Maryland 20892-1460, USA. 10
These authors contributed equally to this work.
Correspondence should be addressed to Clifford J Woolf cwoolf@partners.org 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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