title: Reduction of Neuropathic and Inflammatory Pain through Inhibition of the Tetrahydrobiopterin Pathway.
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.
authors.affiliation: Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alban
authors.initials: A
authors.lastname: Latremoliere
authors.affiliation: 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.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Latini
authors.affiliation: Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nick
authors.initials: N
authors.lastname: Andrews
authors.affiliation: 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.
authors.forename: Shane J
authors.initials: SJ
authors.lastname: Cronin
authors.affiliation: Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Masahide
authors.initials: M
authors.lastname: Fujita
authors.affiliation: Institute of Chemical Sciences and Engineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Gorska
authors.affiliation: Institute of Chemical Sciences and Engineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Ruud
authors.initials: R
authors.lastname: Hovius
authors.affiliation: Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Carla
authors.initials: C
authors.lastname: Romero
authors.affiliation: Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Surawee
authors.initials: S
authors.lastname: Chuaiphichai
authors.affiliation: Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Michio
authors.initials: M
authors.lastname: Painter
authors.affiliation: Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Giulia
authors.initials: G
authors.lastname: Miracca
authors.affiliation: Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Olusegun
authors.initials: O
authors.lastname: Babaniyi
authors.affiliation: 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.
authors.forename: Aline Pertile
authors.initials: AP
authors.lastname: Remor
authors.affiliation: Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Duong
authors.affiliation: Department of Anesthesia, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Priscilla
authors.initials: P
authors.lastname: Riva
authors.affiliation: Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Lee B
authors.initials: LB
authors.lastname: Barrett
authors.affiliation: Pharmazentrum Frankfurt, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Nerea
authors.initials: N
authors.lastname: Ferreirós
authors.affiliation: The Canterbury Consulting Group, Unit 43 Canterbury Innovation Centre, University Road, Canterbury, Kent CT2 7FG, UK.
authors.forename: Alasdair
authors.initials: A
authors.lastname: Naylor
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.affiliation: Pharmazentrum Frankfurt, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Irmgard
authors.initials: I
authors.lastname: Tegeder
authors.affiliation: Burke Medical Research Institute and Brain and Mind Research Institute, Weill Medical College of Cornell University, White Plains, NY 10605, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhong
authors.affiliation: The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: Julian
authors.initials: J
authors.lastname: Blagg
authors.affiliation: Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Channon
authors.affiliation: Institute of Chemical Sciences and Engineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Kai
authors.initials: K
authors.lastname: Johnsson
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Costigan
authors.affiliation: 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.
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Woolf
mesh_terms: D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006136:GTP Cyclohydrolase / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009437:Neuralgia / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D012584:Sciatic Nerve / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism; D012460:Sulfasalazine / Q000627:therapeutic use; D013997:Time Factors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D001708:Biopterins; D012460:Sulfasalazine; D000429:Alcohol Oxidoreductases; C022630:sepiapterin reductase; D006136:GTP Cyclohydrolase; C003402:sapropterin; D015740:Calcitonin Gene-Related Peptide