Wang Dezhi, Li Shanshan, Ma Xianzong, Chen Xi, Tian Xiaoran, Li Xuhang, Chen Linxiao, Kang Qian, Wang Xin, Jin Peng, Lu Xiaojuan, Fu Yanxia, Li Jianghua, Sheng Jianqiu
Department of Gastroenterology, The Seventh Medical Center of PLA General Hospital, Beijing, China.
Department of Laboratory, The Seventh Medical Center of PLA General Hospital, Beijing, China.
Immunopharmacol Immunotoxicol. 2022 Dec;44(6):1044-1057. doi: 10.1080/08923973.2022.2102993. Epub 2022 Jul 25.
Opioid prescription for inflammatory bowel disease (IBD)-related pain is on the rise. However, the use of strong opioids can result in severe complications, and even death, in IBD patients. This study aimed to define the role of fentanyl and morphine, two representative strong opioids, in the pathogenesis of dextran sodium sulfate (DSS)- and 2,4,6-trinitrobenzenesulfonic acid solution (TNBS)-induced colitis.
DSS and TNBS models were induced in C57BL/6J and Balb/c mice, respectively. Disease activity index (DAI), histopathology, enzyme-linked immunosorbent assay (ELISA), multiplex ELISA, and flow cytometry were performed to evaluate the effects of fentanyl and morphine.
Fentanyl exacerbated DSS- and TNBS-induced colitis, while morphine exhibited no significant immunomodulatory effect. Fentanyl and morphine had no obvious effects on the serum levels of adrenocorticotropic hormone (ACTH), glucocorticoid (GC), and prostaglandin E2 (PGE-2) in DSS and TNBS models. Fentanyl elevated the proportions of Th1 cells, μ-opioid receptor (MOR) + Th1 cells, and MOR + macrophages in the colonic mucosa of DSS-treated mice, and enhanced the proportions of Th1 cells, macrophages, MOR + Th1 cells, and MOR + macrophages in the colonic mucosa of TNBS-treated mice. We found that fentanyl upregulated the levels of inflammatory cytokines/chemokines in MOR + macrophages of the colonic lamina propria mononuclear cells (LPMCs) from DSS-treated mice, whereas it had no effect on the expression of most inflammatory cytokines/chemokines in MOR + macrophages in the colonic LPMCs from TNBS-treated mice.
Our findings suggest that fentanyl exacerbates murine colitis Th1 cell- and macrophage-mediated mechanisms, while morphine exhibits no significant immunomodulatory effect.
用于治疗炎症性肠病（IBD）相关疼痛的阿片类药物处方量正在上升。然而，在IBD患者中使用强效阿片类药物可导致严重并发症甚至死亡。本研究旨在确定两种代表性强效阿片类药物芬太尼和吗啡在葡聚糖硫酸钠（DSS）和2,4,6-三硝基苯磺酸溶液（TNBS）诱导的结肠炎发病机制中的作用。
分别在C57BL/6J和Balb/c小鼠中诱导建立DSS和TNBS模型。通过疾病活动指数（DAI）、组织病理学、酶联免疫吸附测定（ELISA）、多重ELISA和流式细胞术来评估芬太尼和吗啡的作用。
芬太尼加剧了DSS和TNBS诱导的结肠炎，而吗啡未表现出明显的免疫调节作用。在DSS和TNBS模型中，芬太尼和吗啡对促肾上腺皮质激素（ACTH）、糖皮质激素（GC）和前列腺素E2（PGE-2）的血清水平无明显影响。芬太尼提高了DSS处理小鼠结肠黏膜中Th1细胞、μ-阿片受体（MOR）+ Th1细胞和MOR +巨噬细胞的比例，并提高了TNBS处理小鼠结肠黏膜中Th1细胞、巨噬细胞、MOR + Th1细胞和MOR +巨噬细胞的比例。我们发现，芬太尼上调了DSS处理小鼠结肠固有层单核细胞（LPMC）中MOR +巨噬细胞的炎性细胞因子/趋化因子水平，而对TNBS处理小鼠结肠LPMC中MOR +巨噬细胞的大多数炎性细胞因子/趋化因子表达无影响。
我们的研究结果表明，芬太尼通过Th1细胞和巨噬细胞介导的机制加剧小鼠结肠炎，而吗啡未表现出明显的免疫调节作用。
