CALLOSAL PROJECTIONS FROM THE PRIMARY SOMATOSENSORY CORTEX ARE ESSENTIAL FOR MIRROR IMAGE PAIN

Mirror-image pain (MIP), characterized by the spread of pain hypersensitivity to the contralateral, uninjured side following unilateral nerve injury, remains a major hurdle in clinical chronic pain management. While central sensitization is known to be involved, the precise cortical circuits facilitating this interhemispheric sensory spread remain elusive. Here, utilizing viral-based tracing and cell-type-specific manipulations, we identify a critical transcallosal circuit within the primary somatosensory cortex (S1) that is essential for MIP. We demonstrate that callosal projection neurons (CPNs) in the contralateral S1 become hyperactive following sciatic nerve chronic constriction injury (CCI), and their activity is indispensable for the development of MIP. Crucially, in vivo recordings reveal a marked suppression of parvalbumin (PV)-expressing inhibitory interneurons in the ipsilateral S1, indicating a state of cortical disinhibition. This loss of inhibition facilitates the recruitment of pyramidal neurons in layer 2/3 and corticospinal neurons in layer 5 within the ipsilateral S1 hindlimb region, both of which are required for the development of MIP. Our findings establish that MIP is mediated by a contralateral S1-driven disinhibitory mechanism in the ipsilateral S1. While this circuit specifically modulates the manifestation of contralateral hypersensitivity rather than the primary injury site, it uncovers a novel transcallosal substrate for therapeutic interventions. Restoring this interhemispheric balance may provide a targeted approach to alleviate the spreading of chronic pain.