Aug 2026· Pain Management· pp.
1-19
· 0 citations· 152 references
Medicine
TL;DR
A narrative review examines clinical, preclinical, and translational studies addressing the role of neuroinflammation in schizophrenia, with a specific focus on microglial and astrocytic activation, cytokine signaling, oxidative stress pathways, and their interactions with central pain processing circuits.
Abstract
INTRODUCTION
Schizophrenia is a chronic and disabling neuropsychiatric disorder traditionally defined by psychotic and cognitive symptoms. Increasing evidence suggests that neuroinflammatory mechanisms contribute to its pathophysiology and may also underlie common but underrecognized somatic manifestations. These include altered pain perception, characterized by both diminished sensitivity and chronic pain, with important implications for functional outcomes and rehabilitation.
AREAS COVERED
This narrative review examines clinical, preclinical, and translational studies addressing the role of neuroinflammation in schizophrenia, with a specific focus on microglial and astrocytic activation, cytokine signaling, oxidative stress pathways, and their interactions with central pain processing circuits. The review was informed by targeted searches of PubMed, Scopus, Web of Science, and Google Scholar, covering articles published from database inception to January 2026, with emphasis on studies relevant to pain modulation, symptom expression, and neurobiological heterogeneity in schizophrenia.
EXPERT OPINION
Neuroinflammation represents a biologically plausible link between core schizophrenia pathology and altered pain perception. Recognition of pain as an integrated component of disease biology, rather than a secondary complaint, may improve clinical assessment and treatment planning. Investigating and targeting neuroinflammatory pathways holds promise for personalized interventions that address neuropsychiatric symptoms and pain, potentially enhancing rehabilitation outcomes and quality of life.
Background/Objectives: Fibromyalgia is a chronic pain condition characterized by widespread musculoskeletal pain, fatigue, sleep disturbance, cognitive dysfunction, and multisensory hypersensitivity. It is increasingly conceptualized as a heterogeneous nociplastic pain condition in which altered nociceptive processing interacts with dysfunctional pain regulation, neuroimmune mechanisms, and variable peripheral contributions. This integrative narrative review aims to synthesize current evidence on the major mechanisms underlying pain in fibromyalgia, with particular emphasis on central sensitization, descending pain modulation, neurochemical dysregulation, small-fiber pathology, neuroimmune processes, and psychobiological modulators. Methods: An integrative narrative review was conducted using iterative, mechanism-oriented searches of the biomedical literature, primarily in PubMed/MEDLINE and complemented by targeted bibliographic searches and reference tracking. Research published up to July 2026 was considered, with emphasis on human mechanistic studies, systematic reviews, meta-analyses, and landmark experimental evidence relevant to the major pathophysiological domains of fibromyalgia. Results: Central sensitization and altered nociceptive gain remain prominent mechanisms of pain amplification in fibromyalgia, but they do not fully account for the clinical phenotype. Evidence also supports impaired and heterogeneous descending pain modulation, neurochemical imbalance, neuroimmune activation, autonomic and stress-system dysregulation, and peripheral contributions, including small-fiber pathology in a substantial subgroup of patients. These mechanisms appear to interact rather than operate independently, while cognitive and emotional factors further modulate symptom severity, persistence, and functional impact. Conclusions: Fibromyalgia is best understood as a heterogeneous nociplastic pain syndrome arising from partially overlapping central, peripheral, neuroimmune, autonomic, and psychobiological mechanisms whose relative contribution varies across patients. Recognizing this mechanistic heterogeneity may improve phenotypic stratification, biomarker development, and the design of more individualized, mechanism-informed therapeutic strategies.
Filipa Martins-Alves, A. Almeida· Biomedicines· 0 citations
Clinical evidence suggests that structured, individualized, and supervised exercise programs may improve mood, cognition, mobility, fatigue, fatigue, and quality of life in individuals with long COVID; however, careful pacing and symptom-contingent adaptation are essential in long COVID to avoid post-exertional symptom exacerbation.
G. Verrienti· Exploration of Neuroscience· 0 citations
Background: Accumulating evidence suggests that bipolar disorder (BD) and epilepsy share important clinical, neurobiological, and therapeutic features. Both disorders are characterized by recurrent episodes and fluctuating clinical courses, raising the possibility that partially overlapping or analogous regulatory processes may contribute to some aspects of their clinical expression and progression. This review examines current evidence regarding the overlap between BD and epilepsy and explores integrative perspectives that may help explain their similarities.
Methods: A narrative review of the literature was conducted. Evidence related to genetics, neuroimaging, cognition, neuroplasticity, neuroinflammation, stress biology, network neuroscience, and treatment response was examined.
Results: Findings across BD and epilepsy reveal partially overlapping biological and clinical features, including alterations in excitation–inhibition balance, neuromodulatory disturbances, neuroinflammatory processes, and neuroplastic changes. Neuroimaging studies in both conditions reveal abnormalities in large-scale brain networks involved in emotional regulation, cognitive control, and behavioral adaptation. Clinically, both disorders show sensitivity to environmental and physiological stressors and sleep disruption, cognitive impairment, and partial responsiveness to overlapping pharmacological and neuromodulatory interventions. These observations are compatible with the hypothesis that recurrent episodes and prolonged network dysregulation may reinforce maladaptive patterns of instability through interacting feedback processes, although this interpretation remains to be tested directly.
Conclusions: Current evidence identifies several clinical and biologicalsimilarities between BD and epilepsy but does not yet establish that these similarities reflect identical or directly shared causal mechanisms. An integrative perspective combining network dysfunction, neuroplasticity, and systemic regulatory processes may provide a useful heuristic framework for investigating disease heterogeneity, progression, and treatment response. Further longitudinal and comparative studies are required before this perspective can support personalized monitoring strategies or mechanism-informed interventions.
R. Gómez-Juanes, Mauro García-Toro, J. Salvà· Actas espanolas de psiquiatr...· 0 citations
Background/Objectives: Neuropathic and chronic centralized pain disorders remain difficult to treat because they involve central sensitization, maladaptive neuroplasticity, neuroimmune activation, affective amplification, and large-scale network dysfunction. Psilocybin, a serotonergic psychedelic acting primarily through 5-HT2A receptor agonism, has emerged as a candidate modulator of chronic pain states; however, clinical evidence remains preliminary. This review synthesizes preclinical, clinical, and mechanistic literature on psilocybin in chronic neuropathic and centralized pain, emphasizing biological plausibility, translational gaps, and future trial design. Methods: PubMed/MEDLINE, Google Scholar, bioRxiv, medRxiv, and targeted journal searches were reviewed through February 2026 and supplemented by reference screening. Thirty-seven peer-reviewed evidence sources were retained for mechanistic synthesis, and ClinicalTrials.gov records were reviewed separately to contextualize the registered clinical-trial landscape. Evidence was synthesized narratively because heterogeneity in study design, pain models, interventions, outcomes, and follow-up precluded meta-analysis. Results: Several preclinical studies reported psilocybin-associated reductions in allodynia, hypersensitivity, formalin-induced nociception, or pain-related affective behaviors in selected rodent models, with some effects linked to 5-HT2A signaling. However, findings were not uniform, and one rigorous null study found no immediate or persistent analgesic effect across multiple models. Human evidence remains limited and is primarily derived from one small open-label fibromyalgia pilot trial, case reports or case series, and survey studies, and has been summarized in recent systematic and narrative reviews. Collectively, these data remain insufficient to establish clinical efficacy. Four putative mechanistic domains were identified: descending serotonergic modulation, 5-HT2A- and TrkB/BDNF-related neuroplasticity, neuroimmune/microglial modulation, and affective-salience/default mode network reorganization. Conclusions: Psilocybin should not currently be regarded as an established analgesic. Available evidence supports a biologically plausible but clinically unproven model requiring phenotype-specific randomized trials with active controls, biomarkers, and long-term follow-up.
M. S. Neves, C. T. P. Gusmão, Raimundo Chiyo et al.· Anesthesia Research· 0 citations
Chronic pain, sleep disturbances, and mental health disorders such as anxiety and depression disorders frequently co-occur, forming a self-reinforcing cycle that impairs daily functioning and quality of life. Chronic pain is driven by peripheral and central sensitization, the latter sustained by reciprocal microglial–astrocytic crosstalk and maladaptive neuroplasticity. Poor sleep amplifies pain through inflammation and circadian disruption. Imbalances in serotonin, dopamine, and norepinephrine, together with limbic alterations and HPA axis dysregulation, contribute to comorbid anxiety and depression. Elevated pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α), NF-κB-driven neuroinflammation, and mitochondrial oxidative stress serve as key molecular links. Building on previous evidence, this review presents an updated triadic, mechanism-based framework describing the reciprocal reinforcement among chronic pain, sleep disturbances, and anxiety and depressive disorders. Consequently, therapeutic strategies targeting inflammatory cytokines, microglial and astrocytic activation, neurotransmitter imbalance, and psychological dysfunction may help address these shared neuroimmune and neuroplastic mechanisms underlying these interconnected disorders.
Boris Burnjaković, Harrison Moy, Aleksandar Sič et al.· International Journal of Mol...· 0 citations
Orofacial pain is a complex and multifactorial condition that affects quality of life and presents important diagnostic and therapeutic challenges. Advances in neuroimaging techniques have enabled the investigation of nervous system alterations associated with pain perception and modulation. This review synthesizes current evidence on structural, functional, and neurochemical brain alterations identified through magnetic resonance imaging (MRI) in individuals with acute and chronic orofacial pain conditions. A comprehensive literature search of PubMed, Web of Science, and Scopus identified MRI studies (structural, diffusion, functional) in adults with temporomandibular disorders, trigeminal neuralgia, persistent dentoalveolar pain, or experimental pain. The main results demonstrated alterations along peripheral trigeminal pathways, brainstem nuclei, and central pain processing networks. Additionally, it was also possible to verify altered gray- and white matter integrity, causing disrupted connectivity within large-scale networks related to pain modulation and cognitive processing. While acute pain reflects transient activation of these pathways, chronic and neuropathic conditions can involve persistent structural and functional reorganization across sensory, affective, and cognitive networks. These findings support the involvement of distributed neural mechanisms and neuroplastic changes in many chronic orofacial pain conditions, while emphasizing that peripheral, central, psychosocial, and contextual factors may contribute to varying degrees across disorders and individuals. Multimodal MRI may provide a basis for future diagnostic, prognostic, and treatment response biomarkers, although most advanced MRI-derived markers remain investigational.
N. Freitas, C. Faria, D. Pozza· Diagnostics· 0 citations
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