Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 4 June 2021 doi:10.20944/preprints202106.0128.v1 Review Co-players in Chronic Pain: Neuroinflammation and the Tryp- tophan-Kynurenine Metabolic Pathway Masaru Tanaka1,2, Nóra Török1,2, Fanni Tóth2, László Vécsei1,2,* 1 MTA-SZTE, Neuroscience Research Group, Semmelweis u. 6, Szeged, H-6725 Hungary 2 Department of Neurology, Interdisciplinary Excellence Centre, Faculty of Medicine, University of Szeged, Semmelweis u. 6, H-6725 Szeged, Hungary * Correspondence: vecsei.laszlo@med.u-szeged.hu; Tel.: +36-62-545-351 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 mechanism of pain, which is due to 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 patho- genesis 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 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 dis- cusses components of the pain pathway, the component-based mechanisms of pain, central and pe- ripheral sensitization, roles of chronic inflammation, and the involvement of tryptophan- kynurenine pathway metabolites, exploring participations of psychosocial and behavioral factors in central sensitization of diseases progressing into 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. Keywords: chronic pain; nociceptive pain; neuropathic pain; nociplastic pain; psychogenic pain; neuroinflammation; kynurenine 1. Introduction Chronic pain is an unpleasant sensory and emotional experience that persists or re- curs more than three months and may extend beyond the expected time of healing [1,2]. Chronic pain occurs as a part of symptoms due to an underlying medical condition or remains despite successful treatment of the condition that originally caused it [3]. Chronic pain frequently becomes the sole or predominant clinical complaint [4]. The prevalence of chronic pain estimates as much as 20% and the incidence reaches about 10% every year of the world adult population [5]. Nearly 10% of individuals with chronic pain was found to suffer from moderate to severe debilitating pain [6]. Furthermore, individuals with severe chronic pain are twice more likely to die of respiratory disease or heart disease than those with mild pain or without pain [5]. The Global Burden of Disease Research ranked low back pain and migraine first and second place of Years Lived with Disability (YLD), re- spectively and thus, chronic pain imposes substantial socioeconomic burden directly and indirectly on society [7]. © 2021 by the author(s). Distributed under a Creative Commons CC BY license. Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 4 June 2021 doi:10.20944/preprints202106.0128.v1 The International Classification of Diseases, Eleventh Revision (ICD-11) classifies chronic pain into primary and secondary. The primary chronic pain is fibromyalgia or low-back pain; the secondary chronic pain occurs secondary to an underlying medical condition subcategorizing into cancer-related, post-trauma, neuropathic, headache and orofacial, visceral, and musculoskeletal pain. ICD-11 offers minimal options for recording psychological or social factors in chronic pain [8]. Meanwhile, Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) recognizes chronic pain in the diagnosis of somatic symptom disorder (SSD), having replaced pain disorder, a condition with chronic pain due to psychological factors [9]. SSD is caused by somatosensory amplifica- tion which is associated with fibromyalgia [10]. The trend toward a neurological explana- tion obviously discounts cognitive, emotional, and social dimensions in the pathomecha- nism of chronic pain. Hyperalgesia is a condition of abnormally increased sensitivity to pain caused by injury to tissues or nerves, or by opioid medication for pain treatment. Hyperalgesia is a challenging issue for pain specialists who treat patients at terminal care [11]. Chronic pain is often elicited by stimuli that previously did not provoke discomfort sensation. It is called allodynia. Allodynia is commonly observed in patients with neurop- athies, fibromyalgia, migraine, complex regional pain syndrome, and postherpetic neu- ralgia [12]. Chronic pain may proceed to clinical conditions accompanied often by mood alterations such as depression, anxiety, anger, cognitive disturbance including memory impairment, sleep disturbances, fatigue, loss of libido, and/or disability, called chronic pain syndrome (CPS). CPS appears to be linked to dysfunction of the hypothalamic–pitu- itary–adrenal axis and the central nervous system (CNS), but exact mechanisms remain unknown [13]. Neuroinflammation has been intricately linked to the pathogenesis of chronic pain. Chronic pain was proposed to be caused by disturbance of peripheral nociception, neu- ropathy in the somatosensory system, motor system, central and peripheral nociplasticity, and/or psychosocial system [14]. Increasing evidence suggests that chronic inflammation is strongly tied to aberration in each mechanism of chronic pain. Furthermore, the trypto- phan (TRP)-kynurenine (KYN) pathway and its metabolites were observed to play an im- portant role in neuroinflammation and chronic pain [15]. This review article presents com- ponents of pain pathway, mechanisms of chronic pain based on the components, devel- opment of chronic pain through peripheral and central sensitization, evidence in presence of chronic neuroinflammation in each pain mechanisms, involvements of the TRP-KYN metabolic pathway, and need of a psychogenic component in the pathogenesis of chronic pain. 2. Pain pathway, Mechanisms, Neuroinflammation, and the Tryptophan Metabolism Pain perception is signaling through the pain pathway whose components consist of transduction, conduction, transmission, modulation, and perception. Transduction is the process by which noxious or potentially damaging stimuli activate the nociceptors to con- vert to neural signals. Transmission refers to the signal transfer from the peripheral neu- rons to the second order neurons in the spinal cord, which wire the signals to the thalamus and brain stem in the brain. Pain modulation takes place by inhibition of pain signaling in the spinal cord and the activation of the descending inhibitory fibers. The third order neurons project to the somatosensory cortex, enabling perception on pain. Perception is the subjective awareness in connection with arousal, physiological, and behavioral brain centers, involving the integration of psychological processes such as attention, expecta- tion, and interpretation [16-18] (Figure 1). Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 4 June 2021 doi:10.20944/preprints202106.0128.v1 Brain (e) Perception (a) Transduction + - - Dorsal Horn Cell Noxious + Stimuli (b) Induction Spinal cord Figure 1. Main components in pain pathway. (a) Transduction, (b) Induction, (c) Trans- mission, (d) Modulation, and (e) Perception. Pain is a complex and intricate process attributable to nociceptic, neuropathic, and/or neuroplastic mechanisms. The most common type of pain is nociceptive pain caused by damage or potentially harmful to peripheral tissues involving nociceptors responsible for transduction. Neuropathic pain is caused by lesions or diseases affecting the somatosen- sory nervous system responsible for transmission of peripheral to central pain signals. Nociplastic pain refers to the condition caused by altered nociceptive processing without actual or potentially harmful tissue damage activating peripheral nociceptors (nociceptive pain) or without lesions or diseases of the somatosensory nervous system (neuropathic pain). Cortical perception is one of the main components in pain pathway, however, the ICD-11 excludes psychogenic pain [19] (Figure 2). Thus, participation of cortical percep- tion in chronic pain mechanisms remains ambiguous. Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 4 June 2021 doi:10.20944/preprints202106.0128.v1 Figure 2. Main components in pain pathway. (a) Transduction, (b) Induction, (c) Trans- mission, (d) Modulation, and (e) Perception. Inflammation is generally involved in the pathogenesis of various diseases and plays a key role in diseases which cause chronic pain [20]. Resident and
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