Co-Players in Chronic Pain: Neuroinflammation and the Tryptophan-Kynurenine Metabolic Pathway

Abstract

Chronic pain is an unpleasant sensory and emotional experience that persists or recurs more than three months and may extend beyond the expected time of healing. Recently, nociplastic pain has been introduced as a descriptor of the mechanism of pain, which is due to the disturbance of neural processing without actual or potential tissue damage, appearing to replace a concept of psychogenic pain. An interdisciplinary task force of the International Association for the Study of Pain (IASP) compiled a systematic classification of clinical conditions associated with chronic pain, which was published in 2018 and will officially come into effect in 2022 in the 11th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-11) by the World Health Organization. ICD-11 offers the option for recording the presence of psychological or social factors in chronic pain; however, cognitive, emotional, and social dimensions in the pathogenesis of chronic pain are missing. Earlier pain disorder was defined as a condition with chronic pain associated with psychological factors, but it was replaced with somatic symptom disorder with predominant pain in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) in 2013. Recently clinical nosology is trending toward highlighting neurological pathology of chronic pain, discounting psychological or social factors in the pathogenesis of pain. This review article discusses components of the pain pathway, the component-based mechanisms of pain, central and peripheral sensitization, roles of chronic inflammation, and the involvement of tryptophan-kynurenine pathway metabolites, exploring the participation of psychosocial and behavioral factors in central sensitization of diseases progressing into the development of chronic pain, comorbid diseases that commonly present a symptom of chronic pain, and psychiatric disorders that manifest chronic pain without obvious actual or potential tissue damage.

The Neurobiological Correlates of Gaze Perception in Healthy Individuals and Neurologic Patients

“…They found that angry faces evoked greater responses in highly anxious participants compared to angry faces with an averted gaze, while the response to fearful faces increased with anxiety for both direct and averted gaze conditions. Recent studies untangled the pathophysiology underlying anxiety disorders: experimental and preclinical evidence revealed that anxiety disorders are determined by the abnormal neural processing of threat-related stimuli, which is mediated by the cyclic AMP (cAMP)-protein kinase A (PKA) pathway [90][91][92]. Additionally, the downregulation of the regulatory subunit of PKA within the amygdala can lead to an augmentation of anxiety-like behavior, resulting in changes in amygdala activation in response to a gaze [93].…”

Kynurenines in the Pathogenesis of Peripheral Neuropathy During Leprosy and COVID-19

“…Despite the lack of studies showing the role of the kynurenine metabolites in COVID-19 pain, many studies have shown its relationship with neuropathic pain and other painful conditions ( Rojewska et al, 2016 ; Rojewska et al, 2018 ; Staats Pires et al, 2020 ; Jovanovic et al, 2020 ; Ciapała et al, 2021 ; Tanaka et al, 2021 ). Some metabolites can act as immunomodulators depending on the dose or the situation, perpetuating low-grade inflammation ( Tanaka et al, 2020 ).…”

Kynurenine Pathway of Tryptophan Metabolism in Migraine and Functional Gastrointestinal Disorders

“…The biogenesis of pain can be underlined by nociceptic, neuropathic, and neuroplastic mechanisms. The kynurenine pathway of L-Trp metabolism may be involved in pain pathogenesis, and the most likely effect associated with this involvement is neuroinflammation (reviewed in [43]). The most common form of pain is nociceptive pain, which is caused by a structural dysfunction, including tissue damage occurring, e.g., in bone fractures (reviewed in [44]).…”