Milk-derived lactoferrin may block tolerance to morphine analgesia
Milk-derived lactoferrin may block tolerance to morphine analgesia
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DOI：
10.1016/j.brainres.2005.11.002
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发表时间：
2006-01-12
期刊：
影响因子：
2.9
通讯作者：
Harada, E
中科院分区：
文献类型：
--
作者：
Tsuchiya, T;Takeuchi, T;Harada, E
乳铁蛋白（LF）是一种多功能蛋白，广泛存在于牛奶、血液和其他生物液体中。在本研究中，我们研究了LF可能阻断小鼠对吗啡诱导的镇痛耐受的可能性。在小鼠甩尾试验中估计了牛乳源性LF （bLF）的伤害效应。虽然腹腔注射（100mg /kg）或口服（300mg /kg） bLF没有明显的镇痛作用，但与腹腔注射吗啡（3mg /kg）联合使用可显著增强吗啡诱导的镇痛作用。此外，3 mg/kg （ip）或5 mg/kg （ip）剂量的吗啡重复给药分别在第5天和第7天引起对吗啡的耐受。相比之下，bLF （100 mg/kg, ip）与吗啡（3 mg/kg, ip）联合使用可延缓小鼠对吗啡的耐受发展至第9天，但bLF对已获得吗啡耐受的小鼠没有任何影响。此外，非选择性一氧化氮合酶（NOS）抑制剂n - g -硝基- l -精氨酸甲酯（L-NAME）预处理可部分阻断bLF的增强作用，选择性神经元NOS （nNOS）抑制剂7-硝基茚唑（7-NI）预处理可完全阻断bLF的增强作用。鸟苷酸环化酶（GC）抑制剂亚甲基蓝（MB）也呈剂量依赖性地阻止了bLF的潜在作用。这些结果表明，bLF选择性地激活nNOS，从而加速NO的产生。一氧化氮的增加反过来调节GC活性，最终通过环鸟苷单磷酸的产生增强内源性阿片系统。我们得出结论，bLF可能通过选择性激活nNOS来阻断小鼠对吗啡耐受的发展。(c) 2005 Elsevier B.V.版权所有
Lactoferrin (LF) is a multifunctional protein that is widely found in milk, blood, and other biological fluids. In the present study, we investigated the possibility that LF may block a tolerance to morphine-induced analgesia in the mouse. The nociceptive effect of bovine milk-derived LF (bLF) was estimated in the mouse tail-flick test. Although an intraperitoneal (100 mg/kg) or an oral (300 mg/kg) administration of bLF did not show remarkable analgesia, a combination with intraperitoneal administration of morphine (3 mg/kg) strikingly enhanced morphine-induced analgesia. Moreover, repeated administration of morphine at doses of 3 mg/kg (ip) or 5 mg/kg (ip) caused a tolerance to the morphine on the 5th or 7th day, respectively. In contrast, the combination of bLF (100 mg/kg, ip) with morphine (3 mg/kg, ip) retarded the development of tolerance to the 9th day, although bLF did not show any effect on the mice that had obtained tolerance to morphine. Furthermore, the potentiative effect of bLF was partially blocked by pre-treatment with N-G-nitro-L-arginine methyl ester (L-NAME), a nonselective nitric oxide synthase (NOS) inhibitor, and completely blocked by 7-nitroindazole (7-NI), a selective neuronal NOS (nNOS) inhibitor. Methylene blue (MB), a guanylate cyclase (GC) inhibitor, also dose-dependently prevented the potentiative effect of bLF. These results suggest that bLF selectively activates nNOS and then accelerates NO production. The increased NO in turn modulates the GC activity and finally enhances the endogenous opioid system via cyclic guanosine monophosphate production. We conclude that bLF may block the development of tolerance to morphine in mice, possibly via the selective activation of nNOS. (c) 2005 Elsevier B.V. All rights reserved.