内源性阿片肽在耐受和血管生成方面的活性研究

发布时间：2018-07-21 16:03

【摘要】： 内源性阿片肽是广泛存在于人和动物体内的一种神经递质和神经调质,具有多种生理学和药理学功能,涉及到镇痛、发育和内分泌、心血管反应、免疫反应和血管生成等。阿片药物在临床上的使用由于其产生耐受、呼吸抑制和便秘等副作用而受到了限制,因此常与其它辅助药物联合使用来降低其副作用。除了中枢神经系统外,血管内皮上也有μ和δ阿片受体的存在,内皮细胞是参与血管生成最重要的分子。本论文研究了褪黑激素对阿片受体激动剂镇痛耐受的影响并且运用体内和体外实验探讨了内源性阿片肽对血管生成的调节作用。结果发现: 1.在小鼠温浴甩尾实验中,连续四天侧脑室注射选择性的μ和δ受体激动剂(内吗啡肽-1和新皮啡肽I)分别能够诱导小鼠产生对药物镇痛的耐受。褪黑激素与受体激动剂联合使用能够剂量依赖地减弱新皮啡肽I产生的镇痛耐受,但是对内吗啡肽-1的镇痛耐受则没有影响。此外,褪黑激素对新皮啡肽I镇痛耐受的减弱能够被选择性MT2受体拮抗剂luzindole所拮抗。这些结果说明褪黑激素通过其自身受体对涉及δ受体激动剂镇痛耐受的神经机制进行了干涉。 2.在鸡胚绒毛尿囊膜(CAM)实验中研究了内源性阿片肽对血管生成的影响。内吗啡肽-1,内吗啡肽-2和新皮啡肽I在1,10,100 nmol/embryo时分别能够剂量依赖地促进CAM的血管生成。非选择阿片受体拮抗剂纳洛酮自身不影响CAM的血管生成,但却能拮抗内源性阿片肽对CAM上血管生成的促进作用。这些结果说明内源性阿片肽(内吗啡肽-1,内吗啡肽-2和新皮啡肽I)能够刺激CAM上的血管生成,而且该作用是通过阿片受体来介导的。 3.此外,在人脐带静脉内皮细胞(HUVEC)的增殖、迁移、粘附和管样结构形成实验中研究了内源性阿片肽对血管生成的调节作用。内吗啡肽-1,内吗啡肽-2和新皮啡肽I在较低剂量能够剂量依赖地促进HUVECs的增殖、迁移、粘附和管样结构的形成;但是在较高剂量它们则表现出抑制作用。单独的纳洛酮不影响HUVECs的增殖、迁移、粘附和管样结构的形成,但却能拮抗内源性阿片肽对血管生成的调节作用。这些数据说明内源性阿片肽(内吗啡肽-1,内吗啡肽-2和新皮啡肽I)还能够通过阿片受体在细胞水平上对血管生成起到调节作用。
[Abstract]:Endogenous opioid peptide is a neurotransmitter and neuromodulator widely present in humans and animals. It has many physiological and pharmacological functions involving analgesia, development and endocrine, cardiovascular response, immune response and angiogenesis. The clinical use of opioids is limited by side effects such as tolerance, respiratory inhibition and constipation, so they are often used in combination with other adjuvant drugs to reduce their side effects. In addition to the central nervous system, there are also 渭 and 未 opioid receptors in vascular endothelium, and endothelial cells are the most important molecules involved in angiogenesis. The effects of melatonin on analgesic tolerance of opioid receptor agonists were studied and the effects of endogenous opioid peptides on angiogenesis were investigated in vivo and in vitro. The results are as follows: 1. In the tail flick test of warm bath in mice, injection of selective 渭 and 未 receptor agonists (endomorphin 1 and neoporphin I) into the lateral ventricle for four consecutive days could induce tolerance to drug analgesia in mice, respectively. Melatonin combined with receptor agonist could attenuate the analgesic tolerance of neoporphin I in a dose-dependent manner, but had no effect on the analgesic tolerance of endomorphin 1. In addition, the decrease of melatonin tolerance to neoporphin I analgesia could be antagonized by selective MT2 receptor antagonist luzindole. These results suggest that melatonin interferes with the neural mechanisms involved in 未 -receptor agonist analgesia tolerance through its own receptors. 2. The effect of endogenous opioid peptide on angiogenesis was studied in chorioallantoic membrane (CAM) of chicken embryo. Endomorphin-1, endomorphin-2 and neoporphin I could promote angiogenesis in a dose-dependent manner at 110 nmol/embryo. Naloxone, a non-selective opioid receptor antagonist, has no effect on angiogenesis in CAM, but can antagonize the angiogenesis of CAM by endogenous opioid peptide. These results suggest that endogenous opioid peptides (endomorphin-1, endomorphin-2 and neoporphin I) can stimulate angiogenesis in CAM, and this effect is mediated by opioid receptors. In addition, the regulation of endogenous opioid peptides on angiogenesis was studied in the proliferation, migration, adhesion and tubular formation of human umbilical vein endothelial cells (HUVEC). Endomorphin-1, endomorphin-2 and neoporphin I could promote the proliferation, migration, adhesion and formation of tubular structure of HUVECs in a dose-dependent manner, but at higher doses they showed inhibitory effects. Naloxone alone did not affect the proliferation, migration, adhesion and formation of tubular structure of HUVECs, but could antagonize the regulation of angiogenesis by endogenous opioid peptides. These data suggest that endogenous opioid peptides (endomorphin-1, endomorphin-2 and neoporphin I) can also regulate angiogenesis at the cellular level through opioid receptors.
【学位授予单位】：兰州大学
【学位级别】：博士
【学位授予年份】：2008
【分类号】：R33;R96

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