<p>Neuropathic pain involves complex cortical mechanisms, yet the role of the medial secondary visual cortex (V2M) remains poorly understood. We hypothesized that glutamatergic neurons in V2M (V2M^Glu) contribute to pain modulation and explored their functional involvement in both normal and neuropathic pain states. Here, we found that V2M^Glu could be activated by peripheral stimulation under normal conditions. Optical inhibition or activation of unilateral V2M^Glu respectively decreased or increased bilateral nociceptive sensitivity, with activation also inducing aversive emotions. Tracing experiments revealed that V2M^Glu sends dense synaptic projections to the lateral posterior thalamic nucleus (LP) and lateral dorsal thalamic nucleus (LD). Notably, only optical manipulation of V2M^Glu terminals in LP, rather than LD, affected bilateral pain perception. Following partial sciatic nerve ligation (PSL), V2M^Glu exhibited hyperactivity, including increased spontaneous spike frequency and heightened responses to stimulation. Inhibiting V2M^Glu alleviated PSL-induced mechanical allodynia, thermal hyperalgesia, and negative affective states related to pain. Inhibition of V2M^Glu terminals in LP mitigated neuropathic pain. Here, we identified V2M^Glu and its circuits to LP as part of the endogenous pain modulatory network, hyperactive after peripheral nerve injury and contributing to neuropathic pain. Our findings support targeting V2M^Glu and related circuits as potential therapeutic strategies for neuropathic pain.</p>