Role of kynurenine and tetrahydrobiopterin pathways in pain hypersensitivity

Chronic pain is a debilitating disease with a devastating socioeconomic impact, yet no efficient and safe treatment is available. One explanation for the limited success of chronic pain management is the inadequate understanding of the molecular mechanisms that underpin chronic pain. Additionally, clinical subjective ratings to evaluate the intensity and other features of chronic pain have played a major role in poor diagnosis and treatment. Thus, objective assessment that can inform about the mechanism underlying chronic pain and support the management of this disease is desired. Current evidence supports immune system activation as a component of chronic pain. Pro-inflammatory mediators are known to be increased during chronic pain conditions. Many of them perpetuate the inflammatory scenario by activating metabolic pathways, including the kynurenine (KYN) and the tetrahydrobiopterin (BH4) pathways, which generate bioactive soluble metabolites with the potential to increase pain sensitivity. Thus, the overarching aim of this thesis was to explore the potential utility of KYN and BH4 pathways-related metabolites as biomarkers of chronic pain. This aim was explored through the evaluation of KYN and BH4 pathways profile and its correlation with chronic pain features in three different cohorts of patients with chronic pain. The arising data reveals that BH4 and the ratio KYN/ tryptophan were directly or indirectly associated with pain intensity across the cohort of chronic pain participants studied. Some of the KYN and BH4 pathways metabolites were correlated with chronic pain features and symptoms, such as depression, stress, and kinesiophobia. Our data showed a reduction of anti-inflammatory cytokines and an increase of pro-inflammatory mediators in the plasma of chronic pain-affected subjects. Additionally, some of the KYN and BH4 pathways metabolites were positively correlated with pro-inflammatory markers, suggesting that immune mediators drive activation of these pathways in chronic pain conditions. Collectively, the data generated in this thesis showed that KYN and BH4 metabolites can be quantified in human body fluids, in a low-invasive manner, as markers of chronic pain and its related features. Based on previous literature and data from our study, it is feasible that KYN and BH4 pathways are also involved in the mechanisms underlying chronic pain. Hence, KYN and BH4 pathways-related metabolites can be proposed as markers of pain that also inform about the pathophysiological mechanisms responsible for chronic pain. The results from this thesis can support future studies and guide the validation of potential biomarker sets for chronic pain that might assist in disease-modifying drugs development and guide the diagnosis, prognosis, and treatment of chronic pain.