A glutamatergic innervation from medial area of secondary visual cortex to lateral posterior thalamic nucleus facilitates nociceptive and neuropathic pain.

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) contribute to pain modulation and explored their functional involvement in both normal and neuropathic pain states. Here, we found that V2M could be activated by peripheral stimulation under normal conditions. Optical inhibition or activation of unilateral V2M respectively decreased or increased bilateral nociceptive sensitivity, with activation also inducing aversive emotions. Tracing experiments revealed that V2M sends dense synaptic projections to the lateral posterior thalamic nucleus (LP) and lateral dorsal thalamic nucleus (LD). Notably, only optical manipulation of V2M terminals in LP, rather than LD, affected bilateral pain perception. Following partial sciatic nerve ligation (PSL), V2M exhibited hyperactivity, including increased spontaneous spike frequency and heightened responses to stimulation. Inhibiting V2M alleviated PSL-induced mechanical allodynia, thermal hyperalgesia, and negative affective states related to pain. Inhibition of V2M terminals in LP mitigated neuropathic pain. Here, we identified V2M 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 and related circuits as potential therapeutic strategies for neuropathic pain.