Cellular Mechanisms Underlying Morphine Analgesic Tolerance and Hyperalgesia

Opioid dose escalation or analgesic tolerance is observed during longer treatments in a significant number of patients with chronic pain owing to cancer or nonmalignant tissue injury. Higher doses of morphine are more likely to result in subsensitivity to the drug and worsened quality of life (QOL) by exerting other side effects. Many investigators have been studying the molecular and cellular mechanisms underlying opioid analgesic tolerance by different approaches. They studied the underlying mechanisms in terms of cellular opioid adaptation following long-term exposure. In so-called cyclic AMP hypothesis in mid1970s, adapted loss of opioid-mediated inhibition of cyclic AMP production and abrupt increase in this level following opioid withdrawal were proposed as mechanistic models for opioid tolerance and dependence, respectively (1–3). In the current cellular models, it is well documented that the molecular events underlying the reduction of opioid receptor function following morphine pretreatments are closely correlated with receptor trafficking, including (i) phosphorylation, (ii) internalization/endocytosis, (iii) sequestration/recycling,