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Development of Opioid Tolerance and Endoplasmic Reticulum Stress

Tomohiko Aoe*

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 tolerance remains uncertain. Opioids bind to the μ opioid receptor (MOR) to activate various signaling molecules, leading to a decrease in neuronal excitability. Chronic morphine tolerance may be derived from adaptations in the intracellular signal transduction of post-MOR activation. 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. Binding immunoglobulin protein (BiP) 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. We also found that a chemical chaperone, which improves ER protein folding capacity, 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.