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.
authors.affiliation: 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.
authors.forename: Irmgard
authors.initials: I
authors.lastname: Tegeder
authors.forename: Michael
authors.initials: M
authors.lastname: Costigan
authors.forename: Robert S
authors.initials: RS
authors.lastname: Griffin
authors.forename: Andrea
authors.initials: A
authors.lastname: Abele
authors.forename: Inna
authors.initials: I
authors.lastname: Belfer
authors.forename: Helmut
authors.initials: H
authors.lastname: Schmidt
authors.forename: Corina
authors.initials: C
authors.lastname: Ehnert
authors.forename: Jemiel
authors.initials: J
authors.lastname: Nejim
authors.forename: Claudiu
authors.initials: C
authors.lastname: Marian
authors.forename: Joachim
authors.initials: J
authors.lastname: Scholz
authors.forename: Tianxia
authors.initials: T
authors.lastname: Wu
authors.forename: Andrew
authors.initials: A
authors.lastname: Allchorne
authors.forename: Luda
authors.initials: L
authors.lastname: Diatchenko
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Binshtok
authors.forename: David
authors.initials: D
authors.lastname: Goldman
authors.forename: Jan
authors.initials: J
authors.lastname: Adolph
authors.forename: Swetha
authors.initials: S
authors.lastname: Sama
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Atlas
authors.forename: William A
authors.initials: WA
authors.lastname: Carlezon
authors.forename: Aram
authors.initials: A
authors.lastname: Parsegian
authors.forename: Jörn
authors.initials: J
authors.lastname: Lötsch
authors.forename: Roger B
authors.initials: RB
authors.lastname: Fillingim
authors.forename: William
authors.initials: W
authors.lastname: Maixner
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.forename: Mitchell B
authors.initials: MB
authors.lastname: Max
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Woolf
mesh_terms: D000328:Adult; D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006136:GTP Cyclohydrolase / Q000037:antagonists & inhibitors / Q000502:physiology*; D006239:Haplotypes; D006801:Humans; D010146:Pain / Q000503:physiopathology*; D059408:Pain Management; D017288:Pain Threshold / Q000502:physiology*; D011446:Prospective Studies; D051381:Rats
chemical_list: D004791:Enzyme Inhibitors; D001708:Biopterins; D000429:Alcohol Oxidoreductases; C022630:sepiapterin reductase; D006136:GTP Cyclohydrolase; C003402:sapropterin