背根神经节中Mrgprd通过NF-κB通路调控阿片类药物所致便秘的机制研究

Mechanistic Study on Mrgprd in the Dorsal Root Ganglia Regulating Opioid-Induced Constipation via the NF-κB Pathway

摘要:

阿片类药物引起的便秘(opioid-induced constipation, OIC)是临床阿片类用药中的常见不良反应,其机制主要涉及肠道外周μ阿片受体(MOR)的激活和局部神经调控。本研究旨在探讨Mrgprd(一种特异性表达于背根神经节的G蛋白偶联受体)在OIC中的作用机制。通过建立40 mg/kg吗啡皮下注射的小鼠OIC模型,并结合Mrgprd基因敲除(KO)小鼠和野生型(WT)小鼠,对便秘相关的行为学指标、肠道组织形态、qPCR技术以及蛋白免疫印迹进行分析。研究发现,Mrgprd缺失显著缓解了OIC模型小鼠的便秘症状,表现为粪便数量和含水量增加,同时肠道黏膜的淋巴细胞浸润显著减少。此外, Mrgprd上调会影响OIC过程中的IL-6释放水平,Mrgprd缺失显著降低了肠道IL-6的上调水平,这一过程是通过NF-κB通路实现的。这表明Mrgprd可能通过调控MOR表达及肠道神经炎症参与OIC的发生。本研究为靶向调节Mrgprd治疗OIC提供了新的理论依据。

Abstract:

Opioid-induced constipation (OIC) is a common adverse effect of clinical opioid medication, and its mechanism mainly involves activation of peripheral μ-opioid receptors (MOR) in the intestine and local neuromodulation. The aim of this study was to investigate the mechanism of Mrgprd, a G protein-coupled receptor specifically expressed in dorsal root ganglia, in OIC. Behavioural indices related to constipation, intestinal histomorphology, qPCR technique, and protein immunoblotting were analysed by establishing a mouse model of OIC with 40 mg/kg morphine subcutaneously injected in combination with Mrgprd knockout (KO) mice and wild-type (WT) mice. It was found that Mrgprd deletion significantly alleviated constipation symptoms in the OIC model mice, as evidenced by an increase in faecal quantity and water content, as well as a significant reduction in lymphocyte infiltration in the intestinal mucosa. In addition, Mrgprd upregulation affects the level of IL-6 release during OIC, and Mrgprd deletion significantly reduced the upregulation of intestinal IL-6, a process that is mediated through the NF-κB pathway. This suggests that Mrgprd may be involved in the development of OIC by regulating MOR expression and intestinal neuroinflammation. This study provides a new theoretical basis for the targeted regulation of Mrgprd for the treatment of OIC.