Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou 221004, China.
Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou 221004, China.
J Neurosci. 2024 Jan 24;44(4):e0869232023. doi: 10.1523/JNEUROSCI.0869-23.2023.
The dorsal raphe nucleus (DRN) is an important nucleus in pain regulation. However, the underlying neural pathway and the function of specific cell types remain unclear. Here, we report a previously unrecognized ascending facilitation pathway, the DRN to the mesoaccumbal dopamine (DA) circuit, for regulating pain. Chronic pain increased the activity of DRN glutamatergic, but not serotonergic, neurons projecting to the ventral tegmental area (VTA) (DRN-VTA) in male mice. The optogenetic activation of DRN-VTA circuit induced a pain-like response in naive male mice, and its inhibition produced an analgesic effect in male mice with neuropathic pain. Furthermore, we discovered that DRN ascending pathway regulated pain through strengthened excitatory transmission onto the VTA DA neurons projecting to the ventral part of nucleus accumbens medial shell (vNAcMed), thereby activated the mesoaccumbal DA neurons. Correspondingly, optogenetic manipulation of this three-node pathway bilaterally regulated pain behaviors. These findings identified a DRN ascending excitatory pathway that is crucial for pain sensory processing, which can potentially be exploited toward targeting pain disorders.
中缝背核（DRN）是疼痛调节中的一个重要核团。然而，其潜在的神经通路和特定细胞类型的功能仍不清楚。在这里，我们报告了一个以前未被识别的上行促进途径，即 DRN 到伏隔核多巴胺（DA）回路，用于调节疼痛。慢性疼痛增加了投射到腹侧被盖区（VTA）的雄性小鼠 DRN 谷氨酸能，但不是 5-羟色胺能神经元的活性（DRN-VTA）。DRN-VTA 回路的光遗传学激活在雄性小鼠中诱导出类似疼痛的反应，其抑制在患有神经病理性疼痛的雄性小鼠中产生镇痛作用。此外，我们发现 DRN 上行通路通过加强投射到伏隔核内侧壳腹侧部分（vNAcMed）的 VTA DA 神经元的兴奋性传递来调节疼痛，从而激活了中隔核 DA 神经元。相应地，双侧光遗传操纵这个三节点通路调节疼痛行为。这些发现确定了 DRN 上行兴奋性通路对疼痛感觉处理至关重要，这可能为靶向疼痛障碍提供了一种潜在的方法。
