BiP, an endoplasmic reticulum chaperone, modulates the development of morphine antinociceptive tolerance.
BiP, an endoplasmic reticulum chaperone, modulates the development of morphine antinociceptive tolerance.
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DOI：
10.1111/j.1582-4934.2009.00932.x
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发表时间：
2010-12
影响因子：
5.3
通讯作者：
Aoe T
中科院分区：
文献类型：
--
作者：
Dobashi T;Tanabe S;Jin H;Mimura N;Yamamoto T;Nishino T;Aoe T
吗啡是一种有效的止痛药，但重复使用后耐受性形成的分子机制尚未完全了解。结合免疫球蛋白（BiP）是内质网（ER）伴侣，对ER功能至关重要。我们研究了基因敲入小鼠表达的突变体BiP与检索序列删除，以阐明生理过程，是敏感的BiP功能。我们在热板试验中测试了吗啡在杂合突变型BiP小鼠中的热抗伤害感受作用。在单次给予吗啡之前和之后，野生型和突变型BiP小鼠之间的缩爪延迟没有显著差异。重复给予吗啡导致野生型小鼠产生吗啡耐受。糖原合成酶激酶3b（glycogen synthase kinase 3b，GSK-3b）的激活与吗啡耐受有关，因为GSK-3β抑制剂阻止了这种激活;另一方面，突变型BiP小鼠表现出较低的吗啡耐受，其脑中GSK-3b的激活受到抑制。这些结果表明BiP在吗啡耐受的形成中可能起重要作用。此外，我们发现，化学伴侣，提高ER蛋白折叠能力也减弱了吗啡耐受性在野生型小鼠的发展，这表明可能的临床应用化学伴侣在预防吗啡耐受。
Morphine is a potent analgesic, but the molecular mechanism for tolerance formation after repeated use is not fully understood. Binding immunoglobulin protein (BiP) is an endoplasmic reticulum (ER) chaperone that is central to ER function. We examined knock-in mice expressing a mutant BiP with the retrieval sequence deleted in order to elucidate physiological processes that are sensitive to BiP functions. We tested the thermal antinociceptive effect of morphine in heterozygous mutant BiP mice in a hot plate test. Paw withdrawal latencies before and after a single administration of morphine were not significantly different between the wild-type and mutant BiP mice. Repeated morphine administration caused the development of morphine tolerance in the wild-type mice. The activation of glycogen synthase kinase 3b (GSK-3b) was associated with morphine tolerance, because an inhibitor of GSK-3β prevented it. On the other hand, the mutant BiP mice showed less morphine tolerance, and the activation of GSK-3b was suppressed in their brain. These results suggest that BiP may play an important role in the development of morphine tolerance. Furthermore, we found that a chemical chaperone which improves ER protein folding capacity also attenuated the development of morphine tolerance in wild-type mice, suggesting a possible clinical application of chemical chaperones in preventing morphine tolerance.
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DOI：
10.1124/jpet.104.066548
发表时间：
2004-08-01
影响因子：
3.5
作者：
Muller, DL;Unterwald, EM
通讯作者：
Unterwald, EM
影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Lin, FT