Ji Ning-Ning, Meng Qing-Xiang, Wang Ying, Zhou Zi-Ming, Song Yu, Hua Rong, Zhang Yong-Mei
Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
Neurobiol Stress. 2022 Apr 21;18:100449. doi: 10.1016/j.ynstr.2022.100449. eCollection 2022 May.
Irritable bowel syndrome (IBS) is a common and debilitating gastrointestinal disorder that is exacerbated by stress and characterized by abdominal pain. Although microglia in the CNS have been implicated as an important mediator of the stress response, the role of microglia and microglia-GABAergic neuron interactions in the limbic area, most notably BNST, in the development of colorectal hypersensitivity has not been determined. We established a neonatal colorectal distension-induced chronic visceral hyperalgesia model in rats. The results showed that the frequency of spontaneous discharges of alBNST GABAergic neurons and the expression of GAD65/67 were significantly decreased in rats with chronic visceral pain. Moreover, ablation of BNST GABAergic neurons significantly reduced the visceral pain threshold in normal rats. Meanwhile, the number of M1 proinflammatory microglia and the expression of the M1 proinflammatory microglia-derived cytokines IL-6 and TNF-α were increased in the alBNST of rats with chronic visceral pain. Furthermore, alBNST infusion of the microglial inhibitor minocycline or IL-6 and TNF-α neutralizing antibodies significantly increased the visceral pain threshold. The decreased frequency of spontaneous discharges of alBNST GABAergic neurons in rats with chronic visceral pain was mimicked by a bath perfusion of TNF-α, but not IL-6, and was abolished by a perfusion of the microglial inhibitor minocycline. In addition, the alBNST infusion of the microglial inhibitor minocycline upregulated the expression of GAD65/67. Moreover, ablation of BNST GABAergic neurons significantly decreased the visceral pain threshold in normal rats, which was not reversed by a subsequent infusion of the microglial inhibitor minocycline. Our findings revealed this microglia-GABAergic neuron circuit in the alBNST, and this microglia-driven disinhibitory mechanism is essential for brain and gut dysfunction in stressful condition, providing a novel potential target for treating patients with IBS presenting visceral pain that is worsened during episodes of stress.
肠易激综合征（IBS）是一种常见且使人衰弱的胃肠道疾病，会因压力而加重，并以腹痛为特征。尽管中枢神经系统中的小胶质细胞被认为是应激反应的重要介质，但小胶质细胞以及边缘区域（最显著的是终纹床核）中与小胶质细胞-γ-氨基丁酸能神经元的相互作用在结直肠超敏反应发展中的作用尚未确定。我们在大鼠中建立了新生期结直肠扩张诱导的慢性内脏痛觉过敏模型。结果表明，慢性内脏痛大鼠终纹床核前部γ-氨基丁酸能神经元的自发放电频率以及谷氨酸脱羧酶65/67（GAD65/67）的表达显著降低。此外，损毁终纹床核前部的γ-氨基丁酸能神经元会显著降低正常大鼠的内脏痛阈值。同时，慢性内脏痛大鼠终纹床核前部M1促炎性小胶质细胞的数量以及M1促炎性小胶质细胞衍生的细胞因子白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）的表达增加。此外，向终纹床核前部注射小胶质细胞抑制剂米诺环素或IL-6和TNF-α中和抗体可显著提高内脏痛阈值。慢性内脏痛大鼠终纹床核前部γ-氨基丁酸能神经元自发放电频率的降低可通过TNF-α的浴灌流模拟，但不能通过IL-6模拟，并且可被小胶质细胞抑制剂米诺环素的灌流消除。此外，向终纹床核前部注射小胶质细胞抑制剂米诺环素会上调GAD65/67的表达。此外，损毁终纹床核前部的γ-氨基丁酸能神经元会显著降低正常大鼠的内脏痛阈值，随后注射小胶质细胞抑制剂米诺环素并不能逆转这一现象。我们的研究结果揭示了终纹床核前部的这种小胶质细胞-γ-氨基丁酸能神经元回路，并且这种小胶质细胞驱动的去抑制机制对于应激状态下脑-肠功能障碍至关重要，为治疗在应激发作期间内脏痛加重的肠易激综合征患者提供了一个新的潜在靶点。
