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A mesocortical glutamatergic pathway modulates neuropathic pain independent of dopamine co-release

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  • Miao Li

    (Columbia University Irving Medical Center)

  • Guang Yang

    (Columbia University Irving Medical Center)

Abstract

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.

Suggested Citation

  • Miao Li & Guang Yang, 2024. "A mesocortical glutamatergic pathway modulates neuropathic pain independent of dopamine co-release," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45035-2
    DOI: 10.1038/s41467-024-45035-2
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    1. Guo-Qiang Wang & Cheng Cen & Chong Li & Shuai Cao & Ning Wang & Zheng Zhou & Xue-Mei Liu & Yu Xu & Na-Xi Tian & Ying Zhang & Jun Wang & Li-Ping Wang & Yun Wang, 2015. "Deactivation of excitatory neurons in the prelimbic cortex via Cdk5 promotes pain sensation and anxiety," Nature Communications, Nature, vol. 6(1), pages 1-16, November.
    2. Kuikui Zhou & Hua Xu & Shanshan Lu & Shaolei Jiang & Guoqiang Hou & Xiaofei Deng & Miao He & Yingjie Zhu, 2022. "Reward and aversion processing by input-defined parallel nucleus accumbens circuits in mice," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
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