Mechanisms of Opioid Tolerance



Mechanisms of Opioid Tolerance Opioid tolerance, defined by decreased analgesic efficacy of opioid analgesics after repeated and prolonged use, is a …

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  1. Mechanisms of Opioid Tolerance
    Opioid tolerance, defined by decreased analgesic efficacy of opioid analgesics after repeated and prolonged use, is a significant clinical problem limiting adequate treatment of pain with opioids, the most effective analgesics available today. After decades of research, multiple mechanisms at molecular, cellular and network levels have been proposed to account for the behavioral observation of opioid analgesic tolerance. Major mechanisms include those mediated by opioid receptor desensitization and internalization, glutamate receptors, chronic opioid-induced hyperalgesia and the cAMP-protein kinase A (PKA) pathway. Phosphorylation-dependent opioid receptor desensitization decreases opioid receptor function and agonist efficacy by uncoupling of opioid receptors from downstream effectors, but its rapid time course and recovery of surface receptor functions may limit its contribution to only the early stage of opioid tolerance. Opioid receptor internalization and subsequent down-regulation, on one hand, decrease receptor density on surface membrane and reduce number of receptors available for agonist activation

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