Glucocorticoid Hormones as Modulators of the Kynurenine Pathway in Chronic Pain Conditions

Abstract

The pathogenesis of chronic pain entails a series of complex interactions among the nervous, immune, and endocrine systems. Defined as pain lasting or recurring for more than 3 months, chronic pain is becoming increasingly more prevalent among the US adult population. Pro-inflammatory cytokines from persistent low-grade inflammation not only contribute to the development of chronic pain conditions, but also regulate various aspects of the tryptophan metabolism, especially that of the kynurenine pathway (KP). An elevated level of pro-inflammatory cytokines exerts similar regulatory effects on the hypothalamic–pituitary–adrenal (HPA) axis, an intricate system of neuro–endocrine–immune pathways and a major mechanism of the stress response. As the HPA axis counters inflammation through the secretion of endogenous cortisol, we review the role of cortisol along with that of exogenous glucocorticoids in patients with chronic pain conditions. Considering that different metabolites produced along the KP exhibit neuroprotective, neurotoxic, and pronociceptive properties, we also summarize evidence rendering them as reliable biomarkers in this patient population. While more in vivo studies are needed, we conclude that the interaction between glucocorticoid hormones and the KP poses an attractive venue of diagnostic and therapeutic potential in patients with chronic pain.

Kynurenine Pathway Metabolites as Potential Biomarkers in Chronic Pain

“…Studies have found that the activation of this pathway results in the production of metabolites that contain pro-inflammatory and pro-nociceptive effects, which in turn can contribute to the development and persistence of chronic pain [ 20 ]. Additionally, disruptions in the kynurenine pathway have also been observed in various chronic pain conditions, suggesting its potential as a biomarker for chronic pain [ 21 ]. Hence, targeting the kynurenine pathway may be a promising therapeutic strategy for treating chronic pain, and identifying biomarkers associated with this pathway could lead to the development of more effective pain management approaches.…”

“…Hence, targeting the kynurenine pathway may be a promising therapeutic strategy for treating chronic pain, and identifying biomarkers associated with this pathway could lead to the development of more effective pain management approaches. In fact, previous attempts at therapeutic interventions have already been made outside of the realm of strictly chronic pain, targeting KP metabolites to address migraine, neuropathic, and sciatic nerve pain in particular [ 21 ]. Furthermore, in prior studies that evaluated KP metabolites as potential pain biomarkers, KP metabolites exhibited greater quantifiability and were more reliably sensitive than their current biomarker counterparts, further reinforcing their potential as a useful biomarker for monitoring and managing chronic pain as well.…”