Early life social isolation stress and pain vulnerability: unraveling neuroimmune mechanisms and central sensitization.

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-pituitary-adrenal (HPA) axis, systemic low-grade inflammation, and immune changes. These changes have been shown to promote persistent microglial activation, astrocytic reactivity, and dysregulated neuron-glia 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