Molecular mechanisms for the development of morphine tolerance.

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 functions. Repeat吗啡给药引起的发展吗啡耐受性的野生型小鼠。糖原合成酶激酶3 β（GSK-3 β）的激活与吗啡耐受性有关，因为GSK-3 β的抑制剂阻止了它的激活。另一方面，突变型BiP小鼠表现出较低的吗啡耐受性，并且GSK-3 β的激活在它们的大脑中受到抑制。这些结果表明BiP在吗啡耐受的形成中可能起重要作用。

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.Repeated morphine administration caused the development of morphine tolerance in the wild-type mice. The activation of glycogen synthase kinase 3beta (GSK-3beta) was associated with morphine tolerance, because an inhibitor of GSK-3beta prevented it. On the other hand, the mutant BiP mice showed less morphine tolerance, and the activation of GSK-3beta was suppressed in their brain. These results suggest that BiP may play an important role in the development of morphine tolerance.