BiP, an endoplasmic reticulum chaperone, modulates the development of morphine antinociceptive tolerance

Abstract

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.

Quality Control in the Early Secretory Pathway Plays Significant Roles in vivo

“…However, the response latencies of the mutant BiP mice after the tenth morphine treatment were significantly longer than those of their wild-type littermates at 30, 45 and 60 min after injection. These results showed that the mutant BiP mice were impaired in the development of morphine tolerance (Dobashi et al, 2010).…”

“…Western blot revealed prominent phosphorylation at Ser9 of GSK3β and less phosphorylation at Tyr216 in the homozygous mutant BiP brain compared to those in the wild-type brain. These results suggested that the mutant BiP lacking the KDEL sequence might attenuate the activation of GSK3β in vivo (Dobashi et al, 2010).…”

“…Chronic morphine administration may cause altered signal transduction through persistent MOR activation. It would be possible that the crosstalk between MOR analgesic signal transduction and BiP-KDEL receptor signal transduction may affect morphine tolerance formation in the mutant BiP mice (Dobashi et al, 2010). The heterozygous mutant BiP mice grew up to be adults and showed apparently normal organ development.…”

“…These results suggested a novel function of BiP on the development of morphine tolerance in vivo. The modulation of morphine analgesia by TUDCA revealed a potential clinical application of chemical chaperones that could modulate ER functions for the prevention of morphine tolerance (Dobashi et al, 2010).…”

“…Morphine is a potent analgesic, but the molecular mechanism for tolerance formation after repeated use is not fully understood. We tested the thermal antinociceptive effect of morphine on the heterozygous mutant BiP mice in order to elucidate physiological processes that were sensitive to BiP functions (Dobashi et al, 2010).…”