Molecular mechanisms for the development of morphine tolerance.

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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.