Sex-specific axon initial segment plasticity underlies cortical hyperexcitability in trigeminal pain

Neuropathic pain results from peripheral lesion, causing maladaptive plasticity and central sensitization. Clinical and preclinical studies demonstrate that modifications of primary sensory cortex (S1) activity are essential for neuropathic pain persistence. Rodent studies report heightened S1 pyramidal cell excitability in neuropathic pain model, the origins of which remain debated. The axon initial segment, the action potential trigger zone, is a major determinant of neuronal excitability and is known to undergo structural changes after neural perturbation but its role in chronic pain is poorly understood and no studies have explored its role in cortical hyperexcitability in chronic pain models. Besides, despite a higher prevalence of chronic pain in women, most of preclinical studies have been conducted in males. By integrating electrophysiology, immunohistochemistry, and computational modeling, this study demonstrates that in a trigeminal neuropathic pain rat model, sex-specific structural plasticity of the axon initial segment enhances the excitability of layer 5 pyramidal cells in the somatosensory cortex, potentially driving network-level hyperactivity.