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A glutamatergic DRN–VTA pathway modulates neuropathic pain and comorbid anhedonia-like behavior in mice

Author

Listed:
  • Xin-Yue Wang

    (University of Science and Technology of China)

  • Wen-Bin Jia

    (University of Science and Technology of China)

  • Xiang Xu

    (University of Science and Technology of China)

  • Rui Chen

    (University of Science and Technology of China)

  • Liang-Biao Wang

    (University of Science and Technology of China)

  • Xiao-Jing Su

    (University of Science and Technology of China)

  • Peng-Fei Xu

    (University of Science and Technology of China)

  • Xiao-Qing Liu

    (University of Science and Technology of China)

  • Jie Wen

    (University of Science and Technology of China)

  • Xiao-Yuan Song

    (University of Science and Technology of China)

  • Yuan-Yuan Liu

    (National Institutes of Health (NIH))

  • Zhi Zhang

    (University of Science and Technology of China)

  • Xin-Feng Liu

    (University of Science and Technology of China)

  • Yan Zhang

    (University of Science and Technology of China)

Abstract

Chronic pain causes both physical suffering and comorbid mental symptoms such as anhedonia. However, the neural circuits and molecular mechanisms underlying these maladaptive behaviors remain elusive. Here using a mouse model, we report a pathway from vesicular glutamate transporter 3 neurons in the dorsal raphe nucleus to dopamine neurons in the ventral tegmental area (VGluT3DRN→DAVTA) wherein population-level activity in response to innocuous mechanical stimuli and sucrose consumption is inhibited by chronic neuropathic pain. Mechanistically, neuropathic pain dampens VGluT3DRN → DAVTA glutamatergic transmission and DAVTA neural excitability. VGluT3DRN → DAVTA activation alleviates neuropathic pain and comorbid anhedonia-like behavior (CAB) by releasing glutamate, which subsequently promotes DA release in the nucleus accumbens medial shell (NAcMed) and produces analgesic and anti-anhedonia effects via D2 and D1 receptors, respectively. In addition, VGluT3DRN → DAVTA inhibition produces pain-like reflexive hypersensitivity and anhedonia-like behavior in intact mice. These findings reveal a crucial role for VGluT3DRN → DAVTA → D2/D1NAcMed pathway in establishing and modulating chronic pain and CAB.

Suggested Citation

  • Xin-Yue Wang & Wen-Bin Jia & Xiang Xu & Rui Chen & Liang-Biao Wang & Xiao-Jing Su & Peng-Fei Xu & Xiao-Qing Liu & Jie Wen & Xiao-Yuan Song & Yuan-Yuan Liu & Zhi Zhang & Xin-Feng Liu & Yan Zhang, 2023. "A glutamatergic DRN–VTA pathway modulates neuropathic pain and comorbid anhedonia-like behavior in mice," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40860-3
    DOI: 10.1038/s41467-023-40860-3
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