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Neuron. 2015 Jun 17;86(6):1393-406. doi: 10.1016/j.neuron.2015.05.033.

Reduction of Neuropathic and Inflammatory Pain through Inhibition of the Tetrahydrobiopterin Pathway.

Author information

1
Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
2
Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; LABOX, Universidade Federal de Santa Catarina, 88040-900 Florianópolis, Brazil.
3
Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
4
Institute of Chemical Sciences and Engineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
5
Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
6
Department of Anesthesia, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
7
Pharmazentrum Frankfurt, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
8
The Canterbury Consulting Group, Unit 43 Canterbury Innovation Centre, University Road, Canterbury, Kent CT2 7FG, UK.
9
Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
10
Burke Medical Research Institute and Brain and Mind Research Institute, Weill Medical College of Cornell University, White Plains, NY 10605, USA.
11
The Institute of Cancer Research, London SW7 3RP, UK.
12
Department of Anesthesia, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: michael.costigan@childrens.harvard.edu.
13
Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: clifford.woolf@childrens.harvard.edu.

Abstract

Human genetic studies have revealed an association between GTP cyclohydrolase 1 polymorphisms, which decrease tetrahydrobiopterin (BH4) levels, and reduced pain in patients. We now show that excessive BH4 is produced in mice by both axotomized sensory neurons and macrophages infiltrating damaged nerves and inflamed tissue. Constitutive BH4 overproduction in sensory neurons increases pain sensitivity, whereas blocking BH4 production only in these cells reduces nerve injury-induced hypersensitivity without affecting nociceptive pain. To minimize risk of side effects, we targeted sepiapterin reductase (SPR), whose blockade allows minimal BH4 production through the BH4 salvage pathways. Using a structure-based design, we developed a potent SPR inhibitor and show that it reduces pain hypersensitivity effectively with a concomitant decrease in BH4 levels in target tissues, acting both on sensory neurons and macrophages, with no development of tolerance or adverse effects. Finally, we demonstrate that sepiapterin accumulation is a sensitive biomarker for SPR inhibition in vivo.

PMID:
26087165
PMCID:
PMC4485422
DOI:
10.1016/j.neuron.2015.05.033
[Indexed for MEDLINE]
Free PMC Article

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