{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T17:58:31Z","timestamp":1787507911723,"version":"build-2736575974"},"reference-count":137,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    Chronic pain is increasingly recognized as a multidimensional condition in which neuroimmune interactions shape disease vulnerability and persistence. Among the emerging pain phenotypes, nociplastic pain (defined as an alteration of nociceptive processing in the absence of clear tissue damage or somatosensory lesion) remains mechanistically elusive and therapeutically challenging. Emerging evidence suggests that early life stress, particularly social isolation, may be a potent psychosocial stressor associated with an increased risk of nociplastic pain. However, this relationship remains incompletely understood and is largely inferred from indirect, model-dependent, or related lines of research. Preclinical and clinical studies indicate that prolonged social isolation can induce sustained activation of the hypothalamic\u2013pituitary\u2013adrenal (HPA) axis, systemic low-grade inflammation, and immune changes. These changes have been shown to promote persistent microglial activation, astrocytic reactivity, and dysregulated neuron\u2013glia communication within pain-processing regions, including the spinal dorsal horn and supraspinal affective circuits. In parallel, peripheral neuroimmune alterations, particularly involving satellite glial cells and Schwann cells may contribute to increased sensory neuron excitability and processes consistent with central sensitization. Notably, much of this evidence derives from studies on stress-related conditions, neuroinflammation, and disorders such as fibromyalgia, rather than being specific to nociplastic pain\n                    <jats:italic>per se<\/jats:italic>\n                    . Early life social isolation stress has also been associated with changes in limbic and prefrontal networks implicated in the affective components of pain, suggesting a potential interaction between emotional dysregulation and pain amplification, although causal pathways remain to be clarified. Sex-dependent differences in neuroimmune signalling further add complexity to this framework, suggesting that biological sex may influence vulnerability to isolation-induced pain states and response to glial-targeted interventions. This narrative review proposes a putative neuroimmune model linking early life social isolation stress to nociplastic pain vulnerability and persistence. By integrating evidence from stress biology, glial dysfunction, and central sensitization, we aim to outline a conceptual model that may help guide future research and inform therapeutic strategies targeting central and peripheral neuroinflammatory processes.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1844087","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T05:24:42Z","timestamp":1780291482000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Early life social isolation stress and pain vulnerability: unraveling neuroimmune mechanisms and central sensitization"],"prefix":"10.3389","volume":"17","author":[{"given":"Carmela","family":"Belardo","sequence":"first","affiliation":[{"name":"Department of Life Science, Health and Health Professions, Link Campus University","place":["Rome, Italy"]},{"name":"Department of Experimental Medicine, University of Campania 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