Reduced hyperalgesia in homozygous carriers of a GTP cyclohydrolase 1 haplotype.
BACKGROUND
Carriers of a particular haplotype of the GTP cyclohydrolase gene (GCH1) had less pain after surgery for chronic lumbar radiculopathy and a decreased sensitivity to some experimental mechanical pain stimuli. Ex-vivo, GCH1 upregulation and BH4 production after forskolin stimulation were reduced, while baseline BH4 concentrations were not affected. This suggested that the haplotype may mainly exert its modulating function when the GCH1 system is provoked. The present study aimed at (i) testing this hypothesis and (ii) independently reproducing the pain-decreasing effects of a particular GCH1 haplotype having been previously associated with pain protection.


METHODS
Experimental pain models with sensitization (local skin inflammation, dermal capsaicin application) and without sensitization (punctate pressure, blunt pressure, thermal and electrical pain) were assessed in 10 homozygous and 22 non-carriers of the particular GCH1 haplotype reportedly associated with pain protection. GCH1, iNOS upregulation and BH4 production were assessed ex-vivo in white blood cells after lipopolysaccharide stimulation for 24 h.


RESULTS
Carriers of the particular GCH1 haplotype addressed in this study had higher thresholds to punctate mechanical pain (von Frey hairs) following local skin inflammation (18.1+/-11.3 vs. 9+/-2.8 g; p=0.005) and, to a lesser degree, to heat pain following capsaicin sensitization (35.2+/-0.9 vs. 36.6+/-2.4 degrees C; p=0.026). In contrast, heat and pressure thresholds and tolerance to electrical stimulation in pain models without sensitization did not differ among the genotypes. GCH1, BH4 and iNOS upregulation in white blood cells after lipopolysaccharide stimulation were decreased in carriers of the GCH1 haplotype, which verified that the genotype groups differed with respect to regulation of the biopterin pathway.


CONCLUSIONS
This study verifies previous results that decreased GCH1 function or inducibility as a result of genetic polymorphisms protects against pain. This study extents previous results by showing that this pain protection is mainly conferred under conditions of hyperalgesia resulting from sensitization, supporting specific functions of BH4 in relation to particular aspects of pain.
Tegeder
Irmgard
I
Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Theodor Stern Kai 7, D-60590 Frankfurt, Germany.
Adolph
Jan
J
Schmidt
Helmut
H
Woolf
Clifford J
CJ
Geisslinger
Gerd
G
Lötsch
Jörn
J
D000328:Adult; D001708:Biopterins / Q000031:analogs & derivatives / Q000096:biosynthesis; D005576:Colforsin / Q000494:pharmacology; D004252:DNA Mutational Analysis; D005260:Female; D006136:GTP Cyclohydrolase / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D006239:Haplotypes / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006930:Hyperalgesia / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D017116:Low Back Pain / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D008297:Male; D019635:Neurosurgical Procedures / Q000009:adverse effects; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology*; D011843:Radiculopathy / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology
D005576:Colforsin; D001708:Biopterins; D006136:GTP Cyclohydrolase; C003402:sapropterin