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

Masaru Tanaka,Nóra Török,László Vécsei,Ágnes Szabó,Fanni Tóth

doi:10.3390/biomedicines9080897

Masaru Tanaka, Nóra Török + Show 3 more

Open Access

https://doi.org/10.3390/biomedicines9080897

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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.

Highlights

Introduction iationsChronic 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 [1,2]
In response to noxious stimuli, the satellite glial cells (SGCs) are activated and proliferated at DRG to release pro-inflammatory cytokines tumor necrosis factor (TNF) and IL-1β and a nociceptive neurotransmitter adenosine triphosphate (ATP) signaling through P2 receptors [61]
The pain pathway, pain mechanisms, inflammation, KYN metabolites and enzymes of the TRP–KYN pathway, and diseases associated with chronic pain are overviewed in this review article

Summary

Transduction and Nociceptive

Painimmune activator lipopolysaccharide, The stress hormone cortisol, the strong. The transduction of thefeedback pain sensation place when stimuli depolarize proinflammatory cytokines, positive loops, takes diminished levelsnoxious of antioxidant the afferent terminal of nociceptive myelinated A-beta (Aß) and system enzyme superoxide dismutase, and anti-inflammatory cytokines allA-delta lead to(Aδ) the fibers and unmyelinated. In addition to mechanical irritation or physical injury, the primary cells unmyelinated C fibers through the terminal membrane proteins and voltage-gated ion of the epidermis, keratinocytes, induce pain by releasing endogenous mediators, such as channels converting them into electric signals in the neurons (Figure 1a). In response to noxious stimuli, the satellite glial cells (SGCs) are activated and proliferated at DRG to release pro-inflammatory cytokines TNF and IL-1β and a nociceptive neurotransmitter ATP signaling through P2 receptors [61]. Bone marrow stem cells trigger analgesic actions by secreting anti-inflammatory cytokine-transforming growth factor-beta 1 by suppressing glial activation induced by nerve injury and migrating to DRG via a (C-X-C motif) chemokine ligand (CXCL) 12 chemotactic signal after intrathecal injection [63]. Following nerve injury, spinal cord neurons upregulate CXCL13 that activates astrocytes via C-C chemokine receptor type 5 to sustain neuropathic pain [67]. Both animal and human studies showed that NMDA antagonist ketamine was beneficial for analgesics [77] (Figure 3)

Modulation and Nociplastic Pain

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Cortical Perception and Psychogenic Pain

Findings

Conclusions and Future Perspective