Hao-Ran Wang1,2,3 • Su-Wan Hu1,2 • Song Zhang1,2,4 • Yu Song1,2 • Xiao-Yi Wang1,2 • Lei Wang1,2 • Yang-Yang Li1,2 • Yu-Mei Yu1,2 • He Liu1,2,5 • Di Liu1,2 • Hai-Lei Ding1,2 • Jun-Li Cao1,2,5

1 Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou 221004, China

2 Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou 221004, China

3 Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital), Nanjing 210029, China

4 Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China

5 Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China

Abstract

Mesocorticolimbic dopaminergic (DA) neurons have been implicated in regulating nociception in chronic pain, yet the mechanisms are barely understood. Here, we found that chronic constructive injury (CCI) in mice increased the firing activity and decreased the KCNQ channel-mediated M-currents in ventral tegmental area (VTA) DA neurons projecting to the nucleus accumbens (NAc). Chemogenetic inhibition of the VTA-to-NAc DA neurons alleviated CCI-induced thermal nociception. Opposite changes in the firing activity and M-currents were recorded in VTA DA neurons projecting to the medial prefrontal cortex (mPFC) but did not affect nociception. In addition, intra-VTA injection of retigabine, a KCNQ opener, while reversing the changes of the VTA-to-NAc DA neurons, alleviated CCI-induced nociception, and this was abolished by injecting exogenous BDNF into the NAc. Taken together, these findings highlight a vital role of KCNQ channel-mediated modulation of mesolimbic DA activity in regulating thermal nociception in the chronic pain state.

Keywords

Nociception; Mesocorticolimbic system; Ventral tegmental area; Brain-derived neurotrophic factor; KCNQ; Retigabine; Chronic neuropathic pain

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