Staats Pires Ananda, Tan Vanessa X, Heng Benjamin, Guillemin Gilles J, Latini Alexandra
Neuroinflammation Group, Department of Biomedical Sciences, Centre for Motor Neuron Disease Research, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia.
Laboratório de Bioenergética e Estresse Oxidativo, Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Brazil.
Front Neurosci. 2020 Jun 24;14:620. doi: 10.3389/fnins.2020.00620. eCollection 2020.
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.
尽管已经确定了与疼痛持续相关的分子机制，但治疗方面并未取得显著进展。对诱导疼痛超敏反应的分子机制的深入理解将有助于开发针对慢性疼痛的新型、有效且安全的疗法。已知多种促炎细胞因子在慢性疼痛期间会增加，导致外周和中枢神经系统持续炎症。促炎环境激活了额外的代谢途径，包括犬尿氨酸（KYN）和四氢生物蝶呤（BH4）途径，这些途径产生具有调节神经性和炎性疼痛敏感性潜力的生物活性可溶性代谢产物。在实验性慢性疼痛模型以及慢性疼痛患者的生物样本中，已发现炎症诱导的吲哚胺2,3-双加氧酶1（IDO1）和鸟苷三磷酸环化水解酶I（GTPCH）上调，它们分别是KYN和BH4生物合成的限速酶。炎症诱导的KYN和BH4途径上调的特征是，除了炎症介质如干扰素γ（IFN-γ）和肿瘤坏死因子α（TNF-α）外，伤害感受性化合物如喹啉酸（QUIN）和BH4增加。不出所料，对这两条途径进行药理和基因实验操作均可产生镇痛作用。已知这两条途径的许多代谢中间体如BH4会维持疼痛，而其他一些物质，如黄尿酸（XA；一种KYN途径代谢产物），最近已被证明是BH4合成的抑制剂，为治疗慢性疼痛开辟了新途径。本综述将聚焦于慢性疼痛中KYN/BH4的相互作用以及这些代谢途径的潜在调节作用，这些调节作用可诱导镇痛且无依赖性或滥用倾向。
