ArticleNeuron2015
Reduction of Neuropathic and Inflammatory Pain through Inhibition of the Tetrahydrobiopterin Pathway.
Article in Neuron, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
66 citing papers in PubMed, 114 citations in OpenAlex.
- Transcriptional regulation of the GTP cyclohydrolase I gene via the NF-κB pathway by bacterial and viral immune stimulants.Journal of biochemistry · 2026Article
- BH4 Oxidation-Derived HJournal of neurochemistry · 2025Article
- Resolution of Lipopolysaccharide-Induced Inflammation Followed by DNA Hypomethylation and Increased Tetrahydrobiopterin Biosynthesis in Mouse Hippocampus.Brain sciences · 2025Article
- Pain Hypersensitivity and Increased Urinary Tetrahydrobiopterin Levels in Mice Submitted to High-Fat Diet.Brain sciences · 2025Article
- Cross-species RNAi therapy via AAV delivery alleviates neuropathic pain by targeting GCH1.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Article
- Emerging role of macrophages in neuropathic pain.Journal of orthopaedic translation · 2025Review
- From a clinically relevant pain target to a possible analgesic treatment strategy.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Article
- Overexpression of miR-133a-3p reduces microglia activation by binding to GCH1, alleviating neuroinflammation and neuropathic pain.Experimental brain research · 2024Article
- Review
- Lysophosphatidic Acid Receptors LPAR5 and LPAR2 Inversely Control Hydroxychloroquine-Evoked Itch and Scratching in Mice.International journal of molecular sciences · 2024Article
- Article
- Nociceptor spontaneous activity is responsible for fragmenting non-rapid eye movement sleep in mouse models of neuropathic pain.Science translational medicine · 2024Article
- Chronic pain after spine surgery: Insights into pathogenesis, new treatment, and preventive therapy.Journal of orthopaedic translation · 2023Review
- Crucial neuroprotective roles of the metabolite BH4 in dopaminergic neurons.bioRxiv : the preprint server for biology · 2023Article
- Implementation of a Drug Screening Platform to TargetBio-protocol · 2023Article
- Tetrahydrobiopterin: Beyond Its Traditional Role as a Cofactor.Antioxidants (Basel, Switzerland) · 2023Review
- Targeted Therapy for Orofacial Pain: A Novel Perspective for Precision Medicine.Journal of personalized medicine · 2023Review
- Article
- Mast cell-derived BH4 is a critical mediator of postoperative pain.bioRxiv : the preprint server for biology · 2023Article
- Artificial Neural Networks Coupled with MALDI-TOF MS Serum Fingerprinting To Classify and Diagnose Pathological Pain Subtypes in Preclinical Models.ACS chemical neuroscience · 2023Article
6 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
26 authors at 7 institutions in 6 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.