Modulation of the development of morphine antinociceptive tolerance by endoplasmic reticulum chaperones

Opioids are potent analgesics, widely used to control acute and chronic pain. While repeated administration of opioids, particularly morphine, induces tolerance that reduces the effectiveness of the analgesic, the precise molecular mechanism for the development of such a tolerance remains uncertain. Opioids bind to the μ opioid receptor (MOR) to activate various signaling molecules, leading to a decrease in neuronal excitability. An activation of MOR also induces its phosphorylation and internalization. The transient uncoupling of MOR from signaling pathways causes opioid desensitization. Most of the internalized MORs return to the cell surface, resulting in resensitization. Chronic morphine tolerance may be derived from adaptations in the intracellular signal transduction of post-MOR activation, as morphine does not induce effective MOR phosphorylation and internalization. Persistent MOR activation on the cell surface may alter signal transduction, including changes in the glycogen synthase kinase 3β (GSK3β) signaling pathway. GSK3β is expressed ubiquitously and is one of the central molecules in intracellular signal transduction. Many physiological and pathological conditions, such as secretory demands, ischemia, hypoxia, and genetic mutations, can cause aberrant protein folding and the accumulation of misfolded proteins in the endoplasmic reticulum (ER). These insults lead to ER stress and initiate the unfolded protein response (UPR). Recent studies have suggested that chronic ER stress might modulate intracellular signaling pathways, resulting in several chronic disorders, such as type II diabetes and interstitial pneumonia. Binding immunoglobulin protein (BiP, or GRP78) is an ER chaperone that is central to ER functioning. Recently, our studies in mice suggest that BiP may play an important role in the development of morphine tolerance, possibly through the modulation of GSK3β signaling. We also found that a chemical chaperone, which improves ER protein folding capacity, attenuated the development of morphine tolerance. Furthermore, a co-administration of valproate, which is supposed to modulate both the GSK3β signaling and the expression of ER chaperones, attenuated the development of morphine tolerance. Thus, the modulation of ER functions by chemical chaperones and other drugs may lead to a new direction for the prevention of morphine tolerance.