Kynurenine and Tetrahydrobiopterin Pathways Crosstalk in Pain Hypersensitivity

Abstract

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 proinflammatory 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.

GCH1 induces immunosuppression through metabolic reprogramming and IDO1 upregulation in triple-negative breast cancer

“…31 Herein, our study identified GCH1 as an alternative immunometabolic target and DAHP as a suppressor of IDO1 expression. Crosstalk between BH4 synthesis and Trp metabolism has been reported previously, 32 33 and concurrent activation of IDO1 and GCH1 was found in chronic inflammation, 34 aging and agingassociated disorders, 35 and hematopoietic stem cells. 36 We hypothesize that the mechanisms behind the IDO1 upregulation by GCH1 overexpression are as follows.…”

The Role of the Kynurenine Signaling Pathway in Different Chronic Pain Conditions and Potential Use of Therapeutic Agents

“…NO regulates the IDO enzyme in three distinct aspects: by preventing IFN-γ-induced expression, by directly inhibiting the IDO, and by degrading the IDO through the proteasome pathway [ 35 ]. Noteworthy, the expression of key regulatory enzymes of kynurenine (IDO-1) and tetrahydrobiopterin (GCH1) pathways is regulated by common pro-inflammatory mediators, such as IFN-γ and LPS [ 36 ]. Pickert et al analyzed the analgesic properties and morphine-related adverse effects of diaminohydroxypyrimidine (DAHP), an inhibitor of guanosine triphosphate cyclohydrolase 1 (GCH1) necessary for BH 4 synthesis, in a mice cancer pain model [ 37 ].…”

The Kynurenine Pathway as a Potential Target for Neuropathic Pain Therapy Design: From Basic Research to Clinical Perspectives

“…The crosstalk between the kynurenine pathway and tetrahydrobiopterin (BH4) pathway has been recently raised as a very important factor in nociception processes. Recently, XA was recognized as an endogenous inhibitor of the BH4 metabolism which raises the possibility that XA can potentially modulate the pathological overproduction of BH4 reported in chronic pain hypersensitivity animal models [126]. Given the dynamically developing research on the role and effect of KP modulators, the possibility for their clinical use in the treatment of various CNS disorders is arousing increasing interest.…”