The opioid receptors play important roles in the regulation of sense and emotions. Although it is recently revealed that opioid receptors are also expressed in various cells, but not restricted in the central nervous system, the effects of opioids on peripheral immune cells are largely unknown. In the current study, we evaluated the effect of opioids on immune system by using selective agonists for δ opioid receptor. Systemic administration of KNT-127 or intraperitoneal injection of YNT-2715 (a KNT-127-related compound that cannot pass through the blood-brain barrier) significantly alleviated the pathology of dextran sodium sulfate-induced colitis. In KNT-127-treated mice, the levels of an inflammatory cytokine IL-6 in the serum, and macrophages in the mesenteric lymph nodes (MLNs) were decreased in the progression stage, and those of regulatory T cells (Tregs) in the MLN were increased in the recovery stage. In vitro experiments revealed that KNT-127 inhibited the release of IL-6 and another inflammatory cytokine TNF-α from macrophages and accelerated the development of Tregs. Our study suggests that δ opioid agonists act directly on immune cells to improve the pathology of the colitis and can be candidates of immunomodulatory drugs.

阿片受体在感觉和情绪的调节中发挥重要作用。尽管最近发现阿片受体也在多种细胞中表达，但不限于中枢神经系统，但阿片类药物对外周免疫细胞的影响很大程度上未知。在当前的研究中，我们通过使用δ阿片受体选择性激动剂来评估阿片类药物对免疫系统的影响。全身给予KNT-127或腹腔注射YNT-2715（一种不能通过血脑屏障的KNT-127相关化合物）可显着缓解右旋糖酐硫酸钠诱导的结肠炎的病理。在 KNT-127 治疗的小鼠中，血清中炎症细胞因子 IL-6 和肠系膜淋巴结 (MLN) 中巨噬细胞的水平在进展阶段降低，MLN 中调节性 T 细胞 (Treg) 的水平降低恢复阶段有所增加。体外实验表明，KNT-127 抑制巨噬细胞释放 IL-6 和另一种炎症细胞因子 TNF-α，并加速 Tregs 的发育。我们的研究表明δ阿片受体激动剂直接作用于免疫细胞以改善结肠炎的病理学，并且可以成为免疫调节药物的候选者。