A glutamatergic S1-VPL-S1 corticothalamocortical loop amplifies mechanical hypersensitivity in neuropathic pain.

Although cortical-thalamic projections contribute to pain modulation, their downstream targets and functional roles are not well defined. Here, we show that glutamatergic neurons in the hindlimb region of primary somatosensory cortex (S1HL Glu ) project to a subset of glutamatergic neurons in the ventral posterolateral thalamic nucleus (VPL Glu ) that are anatomically separated from VPL neurons receiving peripheral afferent inputs. These VPL Glu neurons preferentially innervate S1HL Glu neurons, forming a recurrent glutamatergic corticothalamocortical pathway. Optogenetic and chemogenetic activation of the S1HL Glu -VPL Glu -S1HL Glu pathway reduced mechanical withdrawal thresholds under baseline conditions, whereas circuit inhibition alleviated mechanical allodynia and spontaneous pain in the spared nerve injury model without altering baseline nociception of mice. In vivo fiber photometry further demonstrated that this pathway enhanced S1HL Glu responses to normally subthreshold mechanical stimuli, suggesting a role in sensory amplification. Together, these findings indicate that the S1HL Glu -VPL Glu -S1HL Glu pathway becomes pathologically engaged during neuropathic pain and contributes to mechanical hypersensitivity. This work provides mechanistic insight into corticothalamic involvement in cortical pain processing and highlights a selective excitatory pathway as a potential target for neuropathic pain intervention.