Neuroinflammation, Metabolic Dysfunction, and Chronic Stress Converge on the Insular Cortex in Chronic Pain

Neurosci Biobehav Rev. 2026 Jun 2:106791. doi: 10.1016/j.neubiorev.2026.106791. Online ahead of print.

ABSTRACT

Chronic pain is a prevalent cause of disability worldwide and is increasingly recognized as a complex condition involving alterations in neural processing, emotional regulation, and bodily awareness. Among the brain regions implicated in persistent pain states, the insular cortex has consistently been identified as the most frequently affected cortical region, playing a central role in the integration and interpretation of interoceptive signals. Interoception enables the brain to monitor and regulate internal bodily states, and disruptions in this system may contribute to the persistence of pain by altering how physiological signals are perceived and interpreted. This narrative review synthesizes current evidence linking chronic pain with impaired interoceptive processing and structural and functional alterations in the insular cortex. Particular attention is given to three biological mechanisms capable of affecting insular function and interoception: neuroinflammation and immune signaling, metabolic dysfunction, and chronic activation of stress-related neuroendocrine systems. We also summarize anthropogenic lifestyle exposures that may activate these mechanisms and discuss non-pharmacological strategies capable of modulating them. Integrating these findings within an interoceptive and allostatic framework suggests that chronic pain may partly reflect disturbances in the brain's capacity to accurately interpret and regulate internal bodily states. This perspective may help bridge biological mechanisms with behavioral and lifestyle interventions, opening new avenues for prevention and more comprehensive therapeutic strategies.

PMID:42235664 | DOI:10.1016/j.neubiorev.2026.106791