KCNQ Channels in the Mesolimbic Reward Circuit Regulate Nocic

AAV-hM4D(Gi) and AAV-hM3D(Gq) were used to modulate projection-speciﬁc VTA DA neurons by chemogenetics. AAV-KCNQ2 was used to overexpress KCNQ2 in projection-speciﬁc DA neurons (All viruses were packaged by BrainVTA)

The viruses used in this article from BrainVTA are in the table below

CRE Recombinase	PT-0179 rAAV-TH-NLS-Cre-WPRE-pA
Custom-Made AAVs	rAAV-CMV-DIO-KCNQ2-EGFP
Chemogenetics	PT-0043 rAAV-Eﬂa-DIO-hM4D(Gi)-mCherry-WPRE-pA PT-0042 rAAV-Eﬂa-DIO-hM3D(Gq)-mCherry-WPRE-pA
Control	PT-0012 rAAV-Eﬂa-DIO-EGFP-WPRE-pA

Hao-Ran Wang, Su-Wan Hu, Song Zhang, Yu Song, Xiao-Yi Wang, Lei Wang, Yang-Yang Li, Yu-Mei Yu, He Liu, Di Liu, Hai-Lei Ding, Jun-Li Cao
Pub Date: 2021-04-26, DOI: 10.1007/s12264-021-00668-x, Email: sales@brainvta.com
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.

Figure 1. The VTA-to-NAc, but not the VTA-to-mPFC DA circuit, regulates thermal nociception in CCI mice.

A Mesocorticolimbic dopaminergic (DA) neurons have been implicated in regulating nociception in chronic pain, yet the mechanisms are barely understood. Using electrophysiological, chemogenetics, and pharmacological approaches, the authors explored the roles of the VTA-to-NAc and VTA-to-mPFC DA neurons in an animal model of CCI-induced neuropathic pain and further investigated the underlying cellular mechanism. The ﬁndings highlight a vital role of KCNQ channel-mediated modulation of mesolimbic DA activity in regulating thermal nociception in the chronic pain state.

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