Mechanisms of Opioid Tolerance

Abstract

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. On the other hand, differential ability of various opioid agonists to induce internalization appears to reflect their potency to induce analgesic tolerance, indicating receptor internalization as a key signal for downstream adaptive responses that lead to tolerance. Glutamate receptors, both NMDA and AMPA receptors, have long proved a key component in the synaptic networks responsible for behavioral tolerance, but their detailed role in the network has just begun to emerge. A mechanism of opioid tolerance from a system point of view states that chronic opioids induce sensitized pain, which counteracts the analgesic effect of sustained opioids. Our understanding of the underlying synaptic mechanisms for this counteraction has significantly improved. Finally, although superactivation of the cAMP signaling cascade has long been recognized as a typical molecular adaptation to chronic opioids, its physiological consequences on cell functions and its mechanistic significance for opioid tolerance have been characterized lately.