KCNQ Channels in the Mesolimbic Reward Circuit Regulate Nociception in Chronic Pain in Mice

Hao-Ran Wang,Yu Song,Xiao-Yi Wang,Song Zhang,Yu-Mei Yu,Su-Wan Hu,Jun-Li Cao,Hai-Lei Ding,Di Liu,He Liu,Lei Wang,Yang-Yang Li

doi:10.1007/s12264-021-00668-x

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.

Highlights

Chronic pain has become an enormous health care issue, affecting [15% of the world population [1, 2]
We found that chronic constructive injury (CCI) in mice increased the firing activity and decreased the K? voltage-gated channel subfamily Q (KCNQ) channel-mediated M-currents in ventral tegmental area (VTA) DA neurons projecting to the nucleus accumbens (NAc)
Behavioral results showed that KCNQ2 overexpression in the VTA-to-NAc DA neurons reversed the established thermal hyperalgesia in CCI mice as evidenced by the increased paw withdrawal latency (PWL) (Fig. 5E). This reversal was not seen in the mice with KCNQ2 overexpression in the VTA-to-medial prefrontal cortex (mPFC) DA neurons (Fig. 5G), These results indicate that functional modulation of KCNQ2 channels in the VTA-to-NAc, rather than the VTA-to-mPFC circuit contributes to regulating thermal nociception in chronic neuropathic pain

Summary

Introduction

Chronic pain has become an enormous health care issue, affecting [15% of the world population [1, 2]. The VTA sends DA projections to both limbic and cortical areas and forms two important circuits: the mesolimbic circuit (VTA to the nucleus accumbens, VTA-to-NAc) and the mesocortical circuit (VTA to the medial prefrontal cortex, VTA-to-mPFC) [8, 9]. Both increases and decreases in the firing activity of VTA DA neurons have been reported in chronic pain states [10,11,12]. We speculated that the mesolimbic and mesocortical circuits play different roles in regulating nociceptive responses in chronic pain states

Methods

Results

Conclusion