Sex differences in pain perception and modulation in the brain: effects of insular cortex stimulation on chronic pain relief

Sex-specific differences in brain activation related to chronic pain remain poorly understood. In particular, how stimulation of the insular cortex-a key modulator of pain processing-differentially affects neural pathways in males and females is not well characterized. This study aimed to determine whether insular cortex stimulation activates distinct pain modulation circuits in a sex-dependent manner using a rat model of chronic pain. Understanding these differences may help inform more personalized and effective pain treatment. Neuropathic pain was induced in male and female rats to establish a chronic pain model, followed by insular cortex stimulation. Pain sensitivity was assessed using mechanical allodynia tests to evaluate the behavioural responses. Functional brain connectivity was examined using diffusion tensor imaging, and fractional anisotropy values were calculated across key brain regions. Correlation analyses were conducted between behavioural pain scores and fractional anisotropy values to investigate the relationship between the structural connectivity changes and pain modulation. Under sham conditions, males exhibited lower fractional anisotropy values than females. In the pain condition, both sexes showed reduced fractional anisotropy values; however, females displayed a significantly greater decrease in the ventral posterior thalamic nucleus-amygdala pathway than did males. Following insular cortex stimulation, males showed a more pronounced increase in fractional anisotropy values, with significant sex differences observed in the ventral posterior thalamic nucleus-anterior cingulate cortex, ventral posterior thalamic nucleus-insular cortex, ventral posterior thalamic nucleus-nucleus accumbens, ventral posterior thalamic nucleus-primary somatosensory cortex, primary somatosensory cortex-insular cortex and primary somatosensory cortex-prefrontal cortex pathways. These findings underscore the sex-related differences in brain activation and pain modulation pathways in chronic pain. A deeper understanding of these mechanisms may inform the development of more effective sex-tailored interventions for chronic pain and improve clinical outcomes.