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

Abstract

Tryptophan (TRP) is an essential, aromatic amino acid catabolized by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) enzymes into kynurenine. The IDO enzyme is expressed in peripheral tissues and the central nervous system. Another enzyme of interest in the kynurenine signaling pathway is kynurenine 3-monooxygenase (KMO). The purpose of this review is to discuss the role of TRP and the kynurenine signaling pathway in different chronic pain patients. The IDO-1, IDO-2, and KMO enzymes and the kynurenine metabolite have been shown to be involved in the pathogenesis of neuropathic pain and other painful conditions (migraine, cluster headache, etc.) as well as depressive behavior. We highlighted the analgesic potential of novel agents targeting the enzymes of the kynurenine signaling pathway to explore their efficacy in both future basic science and transitional studies. Upcoming studies conducted on animal models will need to take into consideration the differences in TRP metabolism between human and non-human species. Since chronic painful conditions and depression have common pathophysiological patterns, and the kynurenine signaling pathway is involved in both of them, future clinical studies should aim to have outcomes targeting not only pain, but also functionality, mood changes, and quality of life.

The Role of Interferons in the Pathogenesis of Sjögren’s Syndrome and Future Therapeutic Perspectives

“…As a consequence of these metabolic effects, it has been postulated that the activation of IDO1 may be responsible for some manifestations, like hyperalgesia, WP, and depression, which are frequently encountered in patients with pSS [ 2 , 66 ]. This is supported by the evidence that IDO1 pathway activation, measured by the increased Kyn/Tp ratio in the peripheral blood, has also been observed in other conditions characterized by chronic pain, including fibromyalgia [ 66 , 67 ]. Finally, the increased production of Kyn and Kyn metabolites has been found to be associated with a number of neurological and psychiatric disorders [ 66 ].…”

“…At the opposite pole, there are patients characterized by low prevalence of EGMs, absence or lower level of B activation, and consequently of autoantibodies, and a clinical picture limited to GI and often the presence of chronic pain and depression. One can suppose that type I IFN signature may be milder or absent in this subset and, conversely, type II IFN signature may be predominant and could induce a modulation of immune response via the Treg cell action, and activate other metabolic processes [ 66 , 67 ]. These two patterns of IFN expression are probably more clearly detectable when the analysis is limited to the peripheral blood.…”

Are 5-HT1 receptor agonists effective anti-migraine drugs?

“…The levels of 5-HT and KYNA were significantly increased in the somatosensory cortex, which occurred in narrow time period between 24 and 48 hours, suggesting that a compensatory mechanism is in action to reduce glutamate sensitization and the TVS activation. Thus, the glutamatergic excitotoxicity plays an important role in the pathogenesis of migraine and excitotoxic KYN metabolites certainly contribute to the process [14]. Thus, activation of KYN pathways and their bioactive metabolites play a significant role in the pathogenesis of migraine.…”

Natural Molecules and Neuroprotection: Kynurenic Acid, Pantethine and α-Lipoic Acid

“…A significant reduction in TRP levels in serum and CSF was observed, indicating the activation of KP in MS [ 121 ]. Furthermore, KP activation is a result of cytokines interferon-γ (IFN-γ) and tumor necrosis factor (TNF)-α production, causing IDO-1 expression [ 122 ]. In MS patients’ red blood cells, the KAT I and II activities were significantly higher compared to the controls [ 120 ].…”