Department of Comparative Medicine, Penn State College of Medicine, Hershey, Pennsylvania; Office of Animal Research, The George Washington University, Washington DC;, Email:
Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania; Department of Pharmaceutical & Biomedical Sciences, California Northstate University, Elk Grove, California.
Comp Med. 2020 Feb 1;70(1):25-34. doi: 10.30802/AALAS-CM-19-000024. Epub 2020 Jan 22.
Crohn disease and ulcerative colitis, collectively referred to as inflammatory bowel disease (IBD), are chronic inflammatory disorders of the gastrointestinal tract. Currently, the etiology of IBD is unknown, and immunosuppressive therapies have become the standard of care to reduce the inflammation; however, these agents only induce remission 50% of the time in patients and can have serious side effects. Recently, endogenous opioids and opioid receptors have been shown to play a role in the mediation of inflammation. In addition, opioid receptor blockade with a nonselective antagonist, naltrexone, has been shown to reduce colitis in both murine models and human subjects. The goal of the current study was to determine if the antiinflammatory effects of naltrexone are mediated through the delta (δ) opioid receptor. Male C57BL/6NCrl (6 to 8 wk.; = 110) and female BALB/cAnNCrl (6-8 wk.; = 91) mice were studied using 2 animal models of chemically induced colitis: dextran sodium sulfate (DSS) and 2, 4, 6-trinitrobenzenesulfonic acid (TNBS). The selective δ-receptor antagonists naltrindole and 7-benzylidenenaltrexone were administered to examine the role of the δ-opioid receptor in colonic inflammation. The quantitative measurement of colitis activity, colon weight and length, Hct, WBC count, and gross and microscopic aberrations were analyzed. Administration of naltrexone in the DSS colitis model significantly improved overall disease activity indices on day 5 of therapy. The use of δ-antagonists and naltrexone had limited to no effect on TNBS colitis. Similar findings were obtained by using the DSS colitis model. Based on the current findings, the authors conclude that naltrexone therapy has limited effect on the improvement of colitis in 2 murine models; however, the δ-opioid receptor was not responsible for mediating the effects.
克罗恩病和溃疡性结肠炎，统称为炎症性肠病（IBD），是胃肠道的慢性炎症性疾病。目前，IBD 的病因尚不清楚，免疫抑制疗法已成为减轻炎症的标准治疗方法；然而，这些药物在患者中只有 50%的时间能诱导缓解，并且可能有严重的副作用。最近，内源性阿片肽和阿片受体被证明在炎症的调节中起作用。此外，用非选择性拮抗剂纳曲酮阻断阿片受体已被证明可减少鼠模型和人类受试者的结肠炎。本研究的目的是确定纳曲酮的抗炎作用是否通过 δ（δ）阿片受体介导。使用两种化学诱导结肠炎的动物模型：葡聚糖硫酸钠（DSS）和 2,4,6-三硝基苯磺酸（TNBS），对雄性 C57BL/6NCrl（6-8 周龄；n=110）和雌性 BALB/cAnNCrl（6-8 周龄；n=91）小鼠进行了研究。纳曲酮和 7-苄叉基纳曲酮被用于研究 δ-受体拮抗剂在结肠炎症中的作用。分析了结肠炎活动的定量测量、结肠重量和长度、Hct、白细胞计数以及大体和微观异常。在 DSS 结肠炎模型中，纳曲酮的给药在治疗的第 5 天显著改善了整体疾病活动指数。δ-拮抗剂和纳曲酮的使用对 TNBS 结肠炎的影响有限。使用 DSS 结肠炎模型也得到了类似的发现。基于目前的发现，作者得出结论，纳曲酮治疗对两种鼠模型中结肠炎的改善作用有限；然而，δ-阿片受体并不是介导作用的原因。
