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

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 () and Yan Zhang ()
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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

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40860-3

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