17/05/2025
Hot off the press 🔥
How does chronic psychosocial distress induce pain? Focus on neuroinflammation and neuroplasticity changes
🤕 Chronic primary pain (CPP), particularly fibromyalgia (FM), is a debilitating and poorly understood condition characterized by persistent pain without identifiable peripheral tissue damage. It affects an estimated 2–4% of the population, with a significant predominance in women, and is often accompanied by fatigue, sleep disturbances, and cognitive impairment (Macfarlane et al., 2017; Creed, 2020). Unlike secondary chronic pain, CPP lacks a discernible etiology, making treatment highly challenging.
🧠 A growing body of evidence implicates chronic psychosocial distress as a critical etiological and exacerbating factor (Nicholas et al., 2019; Barke, 2019). Converging clinical and preclinical studies highlight the interplay between stress, neuroinflammation, and altered neuroplasticity as pivotal in the pathogenesis of stress-induced chronic pain (Calcia et al., 2016; DiSabato et al., 2016).
💡 Neuroimmune interactions, particularly involving glial cell activation and inflammatory cytokine release, have emerged as central to this process (Albrecht et al., 2019). These responses are modulated by stress and contribute to both the sensitization of nociceptive pathways and the development of mood disorders, which are frequent comorbidities in CPP patients (Lithwick et al., 2013; Galvez-Sánchez et al., 2019).
📘 A brand-new review by Fülöp et al. (2025) integrates clinical and preclinical findings to elucidate how chronic psychosocial stress drives pain via neuroinflammatory and neuroplastic changes, offering insight into potential therapeutic targets for this complex and unmet medical need.
🔑 Key Points
🧩 Etiology and Challenges of CPP:
Chronic psychosocial distress is the only identified etiological factor for CPP, particularly FM. Classical analgesics are largely ineffective; current therapies rely on antidepressants, antiepileptics, and psychological interventions.
⚖️ Stress-Pain Interaction:
Longitudinal clinical studies demonstrate positive correlations between stress, pain intensity, and psychological comorbidities (Bergenheim et al., 2019; Fillingim et al., 2020). Stress reduces nociceptive thresholds in FM patients, increasing mechanical and thermal sensitivity (Crettaz et al., 2013).
🐁 Animal Models:
Rodent models using chronic stress paradigms (e.g., swim stress, cold stress, restraint stress) replicate FM-like symptoms including hyperalgesia and mood disturbances. These models show increased microglial and astrocyte activation and elevated cytokines such as IL-1 and TNF-α in the central nervous system (Quintero et al., 2003; Fülöp et al., 2023).
🧠 Mood Disorders as Comorbidities:
Depression and anxiety frequently co-occur with FM, exacerbating symptoms and contributing to treatment resistance. These mood disorders share common pathophysiological mechanisms with chronic pain, including stress-induced neuroinflammation and synaptic remodeling (Pagliusi et al., 2020; Liu et al., 2020).
🔬 Neuroinflammation and Neuroplasticity:
PET imaging studies reveal microglial activation in brain regions involved in pain processing in FM patients (Albrecht et al., 2019). Increased functional connectivity within the salience and default mode networks suggests maladaptive neuroplastic changes (McCutcheon et al., 2019; Čeko et al., 2020).
🧪 Molecular Mediators:
Key mediators implicated in these processes include IL-1, brain-derived neurotrophic factor (BDNF), substance P, and hemokinin-1. Experimental evidence indicates that genetic or pharmacological manipulation of these targets in animal models can reduce stress-induced hyperalgesia and mood-related behaviors (Borbély et al., 2023; Jablochkova et al., 2019).
💡 Therapeutic Implications:
Targeting neuroinflammation—particularly through modulation of IL-1 signaling and glial activation—may provide novel approaches for pain management. In addition, studies showing that immunoglobulin G autoantibodies from FM patients can induce pain symptoms in mice suggest a potential autoimmune component in FM pathogenesis (Goebel et al., 2021).
📷 Figure: Chronic psychosocial stress triggers neuroinflammation and neuroplasticity alterations in brain regions like the prefrontal cortex (PFC), amygdala (A), hippocampus (HI), periaqueductal gray (PAG), and somatosensory cortex (SSC), which are also implicated in nociceptive processing, linking chronic pain, mood disorders, and stress.
📒 References
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Barke, A. (2019). Chronic pain has arrived in the ICD-11. International Association for the Study of Pain (IASP).
Bergenheim, A., Juhlin, S., Nordeman, L., Joelsson, M., & Mannerkorpi, K. (2019). Stress levels predict substantial improvement in pain intensity after 10 to 12 years in women with fibromyalgia and chronic widespread pain: A cohort study. BMC Rheumatology, 3, 4. https://doi.org/10.1186/s41927-019-0072-9
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