奖赏环路的中脑腹侧被盖区-中央杏仁核通路参与疼痛缓解的机制研究

Pain contains both sensory and affective dimensions. The latter refers to the negative affects, such as anxiety, fear, and aversion. Pathogenesis of pain sensation has been made progress based on previous literatures. However, mechanisms underlying the negative affects of pain have not been fully identified. As part of the subcortical structure and limbic system, the amygdala is a key player in linking nociceptive stimuli to negative emotional behaviors or affective states. Relief of pain is rewarding. Our preliminary findings suggested that pain relief activates ventral tegmental dopaminergic cells. To determine whether the reward circuit from the ventral tegmental area (VTA) to the central amygdale (CeA) is involved in pain relief, we applied behavioral tests, tract tracing methods, morphology, electrophysiology as well as optogenetics to address mechanisms of pain relief through transmission from the VTA to the CeA. Using a model of experimental postsurgical pain we hypothesize that blockade of afferent input from the injury with local anesthetic will activate ventral tegmental dopaminergic cells, and increase dopamine release in the CeA. Our studies will provide a novel approach for analgesia via controlling the reward circuit. It may provide a new target in future for clinical practice.

痛感觉的研究已取得长足进展，痛情绪的研究相对滞后。杏仁核作为边缘系统的皮质下中枢，在疼痛调制，特别是疼痛情绪反应中起关键作用。疼痛减轻是一种奖赏行为。奖赏环路的中脑腹侧被盖区/VTA→中央杏仁核/CeA是否参与疼痛缓解（奖赏效应）尚未见报道，我们的预实验结果显示VTA区的DA 能神经元在疼痛缓解时活化，因此，本研究以VTA→CeA通路为研究对象，联合应用多种评价动物痛行为的测量手段，以及示踪技术、形态学、分子生物学、光遗传学技术, 探讨VTA区投射到CeA的DA 能神经元在CeA区快速、大量释放DA，激活DA受体缓解疼痛及痛情绪的作用机制（假说）。调控VTA→CeA通路镇痛的作用机制，将为临床缓解疼痛提供新的思路：改变奖赏系统调控疼痛。CeA作为奖赏通路的靶区参与镇痛的机制研究，将为镇痛中枢机制的进一步研究提供理论与实验依据，为新型镇痛药的研发提供新靶点，具有重要的临床应用价值。

疼痛常常伴随有强烈的负性情绪（如焦虑、抑郁、厌恶等）。 杏仁核作为边缘系统的皮质下中枢，在疼痛调制，特别是疼痛情绪反应中起关键作用。疼痛减轻是一种奖赏行为。 本研究发现激活奖赏系统的中脑腹侧被盖区/VTA→中央杏仁核/CeA通路，不仅可缓解切口痛小鼠的机械痛敏、热痛敏，改善痛感觉，而且可缓解切口痛小鼠的自发痛和焦虑样行为，改善疼痛的负性情绪。调控VTA→CeA通路镇痛的作用机制，将为临床治疗疼痛提供新的思路，改变奖赏系统调控疼痛，临床应用前景广阔，具有良好的经济效益和社会效益。本研究还阐明了VTA区投射到CeA的多巴胺能神经元，通过CeA区多巴胺受体D2的下调缓解疼痛及痛情绪的作用机制，不仅为镇痛中枢机制的进一步研究提供理论与实验依据，而且为新型镇痛药的研发提供了新的靶点，具有重要的临床应用价值。