Dysfunction in the mesocortical pathway, connecting the ventral tegmental area (VTA) to the prefrontal cortex, has been implicated in chronic pain. While extensive research has focused on the role of dopamine, the contribution of glutamatergic signaling in pain modulation remains unknown. Using in vivo calcium imaging, we observe diminished VTA glutamatergic activity targeting the prelimbic cortex (PL) in a mouse model of neuropathic pain. Optogenetic activation of VTA glutamatergic terminals in the PL alleviates neuropathic pain, whereas inhibiting these terminals in naïve mice induces pain-like responses. Importantly, this pain-modulating effect is independent of dopamine co-release, as demonstrated by CRISPR/Cas9-mediated gene deletion. Furthermore, we show that VTA neurons primarily project to excitatory neurons in the PL, and their activation restores PL outputs to the anterior cingulate cortex, a key region involved in pain processing. These findings reveal a distinct mesocortical glutamatergic pathway that critically modulates neuropathic pain independent of dopamine signaling.

连接腹侧被盖区 (VTA) 和前额皮质的中皮质通路功能障碍与慢性疼痛有关。虽然广泛的研究集中在多巴胺的作用上，但谷氨酸信号在疼痛调节中的贡献仍然未知。使用体内钙成像，我们观察到神经性疼痛小鼠模型中针对前边缘皮层 (PL) 的 VTA 谷氨酸能活性减弱。 PL 中 VTA 谷氨酸能末端的光遗传学激活可减轻神经性疼痛，而在幼鼠中抑制这些末端会诱导疼痛样反应。重要的是，正如 CRISPR/Cas9 介导的基因删除所证明的那样，这种疼痛调节作用独立于多巴胺的共同释放。此外，我们发现 VTA 神经元主要投射到 PL 中的兴奋性神经元，并且它们的激活恢复了 PL 输出到前扣带皮层（参与疼痛处理的关键区域）。这些发现揭示了一种独特的中皮质谷氨酸能通路，该通路可以独立于多巴胺信号传导来关键地调节神经性疼痛。