Endoplasmic reticulum stress and opioid tolerance withdrawal

Morphine is a potent analgesic, but its molecular mechanism for tolerance formation is not fully understood. Binding immunoglobulin protein (BiP) is an endoplasmic reticulum (ER) chaperone that is central to ER functions. We examined knock-in mice expressing a mutant BiP with the retrieval sequence deleted in order to elucidate physiological BiP functions. We tested thermal antinociceptive effects of morphine on heterozygous mutant BiP mice by a hot plate test. Repeated morphine administration caused the development of morphine tolerance in the wild-type mice. The activation of glycogen synthase kinase 3/3 (GSK3β) was associated with morphine tolerance, since an inhibitor of GSK3β prevented it. On the other hand, the mutant BiP mice showed less morphine tolerance, and the activation of GSK3β 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 that 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.