The locus coeruleus input to the rostral ventromedial medulla mediates stress-induced colorectal visceral pain.
The locus coeruleus input to the rostral ventromedial medulla mediates stress-induced colorectal visceral pain.
复制标题
蓝斑传入延髓头端腹内侧，介导应激性结直肠内脏痛。
DOI：
10.1186/s40478-023-01537-6
复制
发表时间：
2023-04-17
影响因子：
7.1
通讯作者：
Wen, Daxiang
中科院分区：
文献类型：
--
作者：
Kong, Dexu;Zhang, Yunchun;Gao, Po;Pan, Chao;Deng, Haoyue;Xu, Saihong;Tang, Dan;Xiao, Jie;Jiao, Yingfu;Yu, Weifeng;Wen, Daxiang
关键词：
与具有生存价值的生理性应激不同，病理应激在现代社会普遍存在，是内脏疼痛的主要危险因素。作为大脑中主要的应激反应核，蓝斑核（LC）先前已被证明通过直接下行投射到脊髓来驱动疼痛缓解，但LC是否以及如何介导病理性应激性内脏疼痛尚不清楚。在这里，我们发现了从LC去肾上腺素能神经元到鼻侧腹内侧延髓（RVM）的直接电路投射，这是中枢下行疼痛调节系统的一个完整中继。此外，LC-RVM回路的化学发生激活被发现在naïve小鼠中显著诱导结直肠内脏痛觉过敏和焦虑相关精神障碍。在葡聚糖硫酸钠（DSS）诱导的内脏疼痛模型中，小鼠还出现结肠直肠内脏过敏和焦虑相关精神障碍，这与LC-RVM回路的活性增加有关；LC-RVM回路抑制可显著缓解这些症状。此外，慢性约束应激（CRS）模型诱发焦虑相关精神障碍，诱发结直肠内脏痛觉过敏，称为病理性应激性痛觉过敏，抑制LC-RVM回路可减轻结直肠内脏疼痛的严重程度。总的来说，本研究清楚地表明，LC-RVM回路可能对结直肠内脏疼痛和应激相关精神疾病的合并症至关重要。内脏炎症和心理应激均可激活LC去肾上腺素能神经元，通过LC- rvm回路促进结直肠内脏痛觉过敏的严重程度。
Unlike physiological stress, which carries survival value, pathological stress is widespread in modern society and acts as a main risk factor for visceral pain. As the main stress-responsive nucleus in the brain, the locus coeruleus (LC) has been previously shown to drive pain alleviation through direct descending projections to the spinal cord, but whether and how the LC mediates pathological stress-induced visceral pain remains unclear. Here, we identified a direct circuit projection from LC noradrenergic neurons to the rostral ventromedial medulla (RVM), an integral relay of the central descending pain modulation system. Furthermore, the chemogenetic activation of the LC-RVM circuit was found to significantly induce colorectal visceral hyperalgesia and anxiety-related psychiatric disorders in naïve mice. In a dextran sulfate sodium (DSS)-induced visceral pain model, the mice also presented colorectal visceral hypersensitivity and anxiety-related psychiatric disorders, which were associated with increased activity of the LC-RVM circuit; LC-RVM circuit inhibition markedly alleviated these symptoms. Furthermore, the chronic restraint stress (CRS) model precipitates anxiety-related psychiatric disorders and induces colorectal visceral hyperalgesia, which is referred to as pathological stress-induced hyperalgesia, and inhibiting the LC-RVM circuit attenuates the severity of colorectal visceral pain. Overall, the present study clearly demonstrated that the LC-RVM circuit could be critical for the comorbidity of colorectal visceral pain and stress-related psychiatric disorders. Both visceral inflammation and psychological stress can activate LC noradrenergic neurons, which promote the severity of colorectal visceral hyperalgesia through this LC-RVM circuit.