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.
背景组织酸化是炎症、缺血／缺氧、骨质破坏等多种疼痛条件下的共同病理特征。酸敏感离子通道（acid-sensing ion channels，ASICs）是一类兴奋性阳离子通道，表达在神经系统，可直接被细胞外质子激活，介导组织酸化所致的伤害性感受。目的以ASICs为疼痛治疗靶标，将为疼痛治疗提供一条新途径。内容综述ASICs参与组织酸化所致伤害性感受的相关研究。趋向近年来，研究发现ASICs在介导组织酸化所致伤害性感受过程中发挥重要作用，以ASICs为靶点，将为开发新型镇痛药物和疼痛治疗提供新思路。
