Kynurenine and Tetrahydrobiopterin Pathways Crosstalk in Pain Hypersensitivity
Despite the identification of molecular mechanisms associated with pain persistence, no significant therapeutic improvements have been made. Advances in the understanding of the molecular mechanisms that induce pain hypersensitivity will allow the development of novel, effective, and safe therapies...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-06-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnins.2020.00620/full |
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| author | Ananda Staats Pires Ananda Staats Pires Vanessa X. Tan Benjamin Heng Gilles J. Guillemin Alexandra Latini |
| author_facet | Ananda Staats Pires Ananda Staats Pires Vanessa X. Tan Benjamin Heng Gilles J. Guillemin Alexandra Latini |
| author_sort | Ananda Staats Pires |
| collection | DOAJ |
| description | Despite the identification of molecular mechanisms associated with pain persistence, no significant therapeutic improvements have been made. Advances in the understanding of the molecular mechanisms that induce pain hypersensitivity will allow the development of novel, effective, and safe therapies for chronic pain. Various pro-inflammatory cytokines are known to be increased during chronic pain, leading to sustained inflammation in the peripheral and central nervous systems. The pro-inflammatory environment activates additional metabolic routes, including the kynurenine (KYN) and tetrahydrobiopterin (BH4) pathways, which generate bioactive soluble metabolites with the potential to modulate neuropathic and inflammatory pain sensitivity. Inflammation-induced upregulation of indoleamine 2,3-dioxygenase 1 (IDO1) and guanosine triphosphate cyclohydrolase I (GTPCH), both rate-limiting enzymes of KYN and BH4 biosynthesis, respectively, have been identified in experimental chronic pain models as well in biological samples from patients affected by chronic pain. Inflammatory inducible KYN and BH4 pathways upregulation is characterized by increase in pronociceptive compounds, such as quinolinic acid (QUIN) and BH4, in addition to inflammatory mediators such as interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α). As expected, the pharmacologic and genetic experimental manipulation of both pathways confers analgesia. Many metabolic intermediates of these two pathways such as BH4, are known to sustain pain, while others, like xanthurenic acid (XA; a KYN pathway metabolite) have been recently shown to be an inhibitor of BH4 synthesis, opening a new avenue to treat chronic pain. This review will focus on the KYN/BH4 crosstalk in chronic pain and the potential modulation of these metabolic pathways that could induce analgesia without dependence or abuse liability. |
| first_indexed | 2024-12-22T04:42:13Z |
| format | Article |
| id | doaj.art-3a8cf42d9fc34a53a0c74dbd3cf654f0 |
| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-12-22T04:42:13Z |
| publishDate | 2020-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj.art-3a8cf42d9fc34a53a0c74dbd3cf654f02022-12-21T18:38:42ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2020-06-011410.3389/fnins.2020.00620518534Kynurenine and Tetrahydrobiopterin Pathways Crosstalk in Pain HypersensitivityAnanda Staats Pires0Ananda Staats Pires1Vanessa X. Tan2Benjamin Heng3Gilles J. Guillemin4Alexandra Latini5Neuroinflammation Group, Department of Biomedical Sciences, Centre for Motor Neuron Disease Research, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, AustraliaLaboratório de Bioenergética e Estresse Oxidativo, Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, BrazilNeuroinflammation Group, Department of Biomedical Sciences, Centre for Motor Neuron Disease Research, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, AustraliaNeuroinflammation Group, Department of Biomedical Sciences, Centre for Motor Neuron Disease Research, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, AustraliaNeuroinflammation Group, Department of Biomedical Sciences, Centre for Motor Neuron Disease Research, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, AustraliaLaboratório de Bioenergética e Estresse Oxidativo, Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, BrazilDespite the identification of molecular mechanisms associated with pain persistence, no significant therapeutic improvements have been made. Advances in the understanding of the molecular mechanisms that induce pain hypersensitivity will allow the development of novel, effective, and safe therapies for chronic pain. Various pro-inflammatory cytokines are known to be increased during chronic pain, leading to sustained inflammation in the peripheral and central nervous systems. The pro-inflammatory environment activates additional metabolic routes, including the kynurenine (KYN) and tetrahydrobiopterin (BH4) pathways, which generate bioactive soluble metabolites with the potential to modulate neuropathic and inflammatory pain sensitivity. Inflammation-induced upregulation of indoleamine 2,3-dioxygenase 1 (IDO1) and guanosine triphosphate cyclohydrolase I (GTPCH), both rate-limiting enzymes of KYN and BH4 biosynthesis, respectively, have been identified in experimental chronic pain models as well in biological samples from patients affected by chronic pain. Inflammatory inducible KYN and BH4 pathways upregulation is characterized by increase in pronociceptive compounds, such as quinolinic acid (QUIN) and BH4, in addition to inflammatory mediators such as interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α). As expected, the pharmacologic and genetic experimental manipulation of both pathways confers analgesia. Many metabolic intermediates of these two pathways such as BH4, are known to sustain pain, while others, like xanthurenic acid (XA; a KYN pathway metabolite) have been recently shown to be an inhibitor of BH4 synthesis, opening a new avenue to treat chronic pain. This review will focus on the KYN/BH4 crosstalk in chronic pain and the potential modulation of these metabolic pathways that could induce analgesia without dependence or abuse liability.https://www.frontiersin.org/article/10.3389/fnins.2020.00620/fullchronic painneuropathic paininflammatory painneuroinflammationkynureninetetrahydrobiopterin |
| spellingShingle | Ananda Staats Pires Ananda Staats Pires Vanessa X. Tan Benjamin Heng Gilles J. Guillemin Alexandra Latini Kynurenine and Tetrahydrobiopterin Pathways Crosstalk in Pain Hypersensitivity Frontiers in Neuroscience chronic pain neuropathic pain inflammatory pain neuroinflammation kynurenine tetrahydrobiopterin |
| title | Kynurenine and Tetrahydrobiopterin Pathways Crosstalk in Pain Hypersensitivity |
| title_full | Kynurenine and Tetrahydrobiopterin Pathways Crosstalk in Pain Hypersensitivity |
| title_fullStr | Kynurenine and Tetrahydrobiopterin Pathways Crosstalk in Pain Hypersensitivity |
| title_full_unstemmed | Kynurenine and Tetrahydrobiopterin Pathways Crosstalk in Pain Hypersensitivity |
| title_short | Kynurenine and Tetrahydrobiopterin Pathways Crosstalk in Pain Hypersensitivity |
| title_sort | kynurenine and tetrahydrobiopterin pathways crosstalk in pain hypersensitivity |
| topic | chronic pain neuropathic pain inflammatory pain neuroinflammation kynurenine tetrahydrobiopterin |
| url | https://www.frontiersin.org/article/10.3389/fnins.2020.00620/full |
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