The Role of Neuro-Immune Interaction in Chronic Pain Conditions; Functional Somatic Syndrome, Neurogenic Inflammation, and Peripheral Neuropathy

Abstract

Functional somatic syndromes are increasingly diagnosed in chronically ill patients presenting with an array of symptoms not attributed to physical ailments. Conditions such as chronic fatigue syndrome, fibromyalgia syndrome, or irritable bowel syndrome are common disorders that belong in this broad category. Such syndromes are characterised by the presence of one or multiple chronic symptoms including widespread musculoskeletal pain, fatigue, sleep disorders, and abdominal pain, amongst other issues. Symptoms are believed to relate to a complex interaction of biological and psychosocial factors, where a definite aetiology has not been established. Theories suggest causative pathways between the immune and nervous systems of affected individuals with several risk factors identified in patients presenting with one or more functional syndromes. Risk factors including stress and childhood trauma are now recognised as important contributors to chronic pain conditions. Emotional, physical, and sexual abuse during childhood is considered a severe stressor having a high prevalence in functional somatic syndrome suffers. Such trauma permanently alters the biological stress response of the suffers leading to neuroexcitatory and other nerve issues associated with chronic pain in adults. Traumatic and chronic stress results in epigenetic changes in stress response genes, which ultimately leads to dysregulation of the hypothalamic-pituitary axis, the autonomic nervous system, and the immune system manifesting in a broad array of symptoms. Importantly, these systems are known to be dysregulated in patients suffering from functional somatic syndrome. Functional somatic syndromes are also highly prevalent co-morbidities of psychiatric conditions, mood disorders, and anxiety. Consequently, this review aims to provide insight into the role of the nervous system and immune system in chronic pain disorders associated with the musculoskeletal system, and central and peripheral nervous systems.

The Association between Dysbiosis and Neurological Conditions Often Manifesting with Chronic Pain

“…An imbalance in the gut microbiota and microbiome has been established in the aetiology of many intestinal and extra intestinal diseases, including inflammatory bowel diseases (IBD) coeliac disease, irritable bowel syndrome (IBS), colon cancer, liver and pancreas disorders [ 32 ]. Dysbiosis results in leaky gut, visceral hypersensitivity, immune activation, inflammation, mood disorders and chronic fatigue in patients [ 5 ]. Research suggests that increased abundance of Parcubacteria and lower Verrucomicrobia results in neuropathic pain and anhedonia (loss of pleasure) in test rats [ 33 ].…”

“…Many of the intestinal microbes produce neurotransmitters, including acetylcholine produced by Lactobacillus plantarum , dopamine produced by Proteus vulgaris , Bacillus , and Serratia marcescens , GABA produced by Lactobacillus and Bifidobacterium , histamine produced by Citrobacter and Enterobacter , norepinephrine produced by Saccharomyces , Bacillus , and E. coli and serotonin (5-HT) by E. coli , Enterococcus , Candida and Streptococcus [ 36 ]. Therefore, the reduced microbial diversity observed in dysbiosis alters the expression of neurotransmitters affecting the local enteric nervous system and the CNS [ 5 ].…”

“…The GBA has varied routes of communication utilising endocrine, immune and neural mechanisms, which the microbiota is capable of agonising to influence the CNS and can lead to pain associated with neuroinflammation [ 47 ]. The GBA is influenced by the resident microbiota via the secretion of neuroactive biologics, including serotonin, dopamine, acetylcholine and γ-aminobutyric acid (GABA) [ 5 ]. Specifically, intestinal species, including Escherichia spp.…”

“…There are many categories and types of pain, including neuropathic, nociceptive, musculoskeletal, inflammatory, psychogenic and mechanical [ 4 ]. Additional types of chronic pain are categorised into functional somatic syndromes (FSS) where chronic pain persists in the absence of any physical or structural defect in the body or absence of a somatic condition [ 5 ]. Chronic pain is multifaceted, having a significant impact on the suffering individual socially, economically and physically, and affects approximately 20% of the global population [ 2 ].…”

Satellite glial cells drive the transition from acute to chronic pain in a rat model of hyperalgesic priming

“…Chronic pain is one of the most common clinical syndromes in humans and is characterized by plastic changes in the peripheral nervous system (PNS) and central nervous system (CNS), also called peripheral and central sensitization ( Ji et al, 2018 ; Vincent, 2020 ). A vast number of functional proteins and signaling pathways have been reported to be altered or changed in the peripheral neurons in mammals with chronic pain ( Meade and Garvey, 2022 ; Zheng et al, 2022 ). They are thought to contribute to chronic pain directly or indirectly and might be targets for pain treatment ( Berta et al, 2017 ).…”