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

Alban Latremoliere, Alexandra Latini, Nick Andrews, Shane J. Cronin, Masahide Fujita, Katarzyna Gorska, Ruud Hovius, Carla Romero, Surawee Chuaiphichai, Michio Painter, Giulia Miracca, Olusegun Babaniyi, Aline Pertile Remor, Kelly Duong, Priscilla Riva, Lee B. Barrett, Nerea Ferreirós, Alasdair Naylor, Josef M. Penninger, Irmgard TegederJian Zhong, Julian Blagg, Keith M. Channon, Kai Johnsson, Michael Costigan, Clifford J. Woolf

Research output: Contribution to journalArticlepeer-review

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. Video Abstract: Latremoliere et al. genetically manipulated the tetrahydrobiopterin synthesis pathway to formally validate its role in neuropathic and inflammatory pain hypersensitivity, and show that systemic inhibition of this pathway by targeting sepiapterin reductase reduces chronic pain with no adverse effects.

Original languageEnglish (US)
Pages (from-to)1393-1406
Number of pages14
JournalNeuron
Volume86
Issue number6
DOIs
StatePublished - Jun 17 2015
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)

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