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1 Experimental Pharmacology, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, Københavns Universitet 2 Department of Drug Design and Pharmacology, Faculty of Pharmaceutical Sciences, Københavns Universitet 3 Drug Research Academy B, Drug Research Academy, Faculty of Pharmaceutical Sciences, Københavns Universitet 4 Århus Universitets Hospital 5 Institut for Lægemiddeldesign og Farmakologi 6 Institut for Lægemiddeldesign og Farmakoloig 7 Copenhagen University Hospital 8 Drug Research Academy B, Drug Research Academy, Faculty of Pharmaceutical Sciences, Københavns Universitet 9 Experimental Pharmacology, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, Københavns Universitet
Background: GTP cyclohydrolase 1 (GTP-CH1), the rate-limiting enzyme in the synthesis of tetrahydrobiopterin (BH4), encoded by the GCH1 gene, has been implicated in the development and maintenance of inflammatory pain in rats. In humans, homozygous carriers of a " pain-protective" (PP) haplotype of the GCH1 gene have been identified exhibiting lower pain sensitivity, but only following pain sensitisation. Ex vivo, the PP GCH1 haplotype is associated with decreased induction of GCH1 after stimulation, whereas the baseline BH4 production is not affected. Contrary, loss of function mutations in the GCH1 gene results in decreased basal GCH1 expression, and is associated with DOPA-responsive dystonia (DRD). So far it is unknown if such mutations affect acute and inflammatory pain.Results: In the current study, we examined the involvement of the GCH1 gene in pain models using the hyperphenylalaninemia 1 (hph-1) mouse, a genetic model for DRD, with only 10% basal GTP-CH1 activity compared to wild type mice. The study included assays for determination of acute nociception as well as models for pain after sensitisation. Pain behavioural analysis of the hph-1 mice showed reduced pain-like responses following intraplantar injection of CFA, formalin and capsaicin; whereas decreased basal level of GTP-CH1 activity had no influence in naïve hph-1 mice on acute mechanical and heat pain thresholds. Moreover, the hph-1 mice showed no signs of motor impairment or dystonia-like symptoms.Conclusions: In this study, we demonstrate novel evidence that genetic mutations in the GCH1 gene modulate pain-like hypersensitivity. Together, the present data suggest that BH4 is not important for basal heat and mechanical pain, but they support the hypothesis that BH4 plays a role in inflammation-induced hypersensitivity. Our studies suggest that the BH4 pathway could be a therapeutic target for the treatment of inflammatory pain conditions. Moreover, the hph-1 mice provide a valid model to study the consequence of congenital deficiency of GCH1 in painful conditions. © 2013 Nasser et al.; licensee BioMed Central Ltd.
Molecular Pain, 2013, Vol 9, Issue 1
Journal Article; Research Support, Non-U.S. Gov't
Main Research Area: