GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence.
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.
Tegeder
Irmgard
I
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.
Costigan
Michael
M
Griffin
Robert S
RS
Abele
Andrea
A
Belfer
Inna
I
Schmidt
Helmut
H
Ehnert
Corina
C
Nejim
Jemiel
J
Marian
Claudiu
C
Scholz
Joachim
J
Wu
Tianxia
T
Allchorne
Andrew
A
Diatchenko
Luda
L
Binshtok
Alexander M
AM
Goldman
David
D
Adolph
Jan
J
Sama
Swetha
S
Atlas
Steven J
SJ
Carlezon
William A
WA
Parsegian
Aram
A
Lötsch
Jörn
J
Fillingim
Roger B
RB
Maixner
William
W
Geisslinger
Gerd
G
Max
Mitchell B
MB
Woolf
Clifford J
CJ
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
D004791:Enzyme Inhibitors; D001708:Biopterins; D000429:Alcohol Oxidoreductases; C022630:sepiapterin reductase; D006136:GTP Cyclohydrolase; C003402:sapropterin