Neuropathic pain-like responses in a chronic CNS injury model are mediated by corticospinal-targeted spinal interneurons.

Chronic neuropathic pain is a persistent and debilitating outcome of traumatic central nervous system injury, affecting up to 80% of individuals. Post-injury pain is refractory to treatments due to the limited understanding of the brain-spinal cord circuits that underlie pain signal processing. The corticospinal tract (CST) plays critical roles in sensory modulation during skilled movements and tactile sensation; however, a direct role for the CST in injury-associated neuropathic pain is unclear. Here we show that complete, selective CST transection at the medullary pyramids leads to hyperexcitability within lumbar deep dorsal horn and hindlimb allodynia-like behavior in chronically injured adult male and female mice. Chemogenetic regulation of CST-targeted lumbar spinal interneurons demonstrates that dysregulation of activity in this circuit underlies the development of tactile allodynia in chronic injury. Our findings shed light on an unrecognized circuit mechanism implicated in CNS injury-induced neuropathic pain and provide a novel target for therapeutic intervention.Significance Statement CNS injury-induced neuropathic pain affects millions of people worldwide. A significant challenge in developing efficient therapeutics is the lack of suitable animal models that accurately replicate key features of human conditions, such as chronic onset of allodynia. We found a nuanced temporal evolution of sensory responses following a selective corticospinal tract (CST) lesion. Initially, there was a reduced tactile response, which later progressed to an exaggerated response characterized by increased mechanical hypersensitivity, a key feature of allodynia. We further identified a heterogenous population of CST-targeted spinal interneurons in the deep dorsal horn that modulate tactile sensory responses. These findings reveal a pivotal role for the CST in the development of CNS injury-induced chronic neuropathic pain.