Clinical Assessment Tools

Abstract

Opioid dose escalation or analgesic tolerance is observed during longer treat-ments in a significant number of patients with chronic pain owing to cancer ornonmalignant tissue injury. Higher doses of morphine are more likely to result insubsensitivity to the drug and worsened quality of life (QOL) by exerting otherside effects. Many investigators have been studying the molecular and cellularmechanisms underlying opioid analgesic tolerance by different approaches.They studied the underlying mechanisms in terms of cellular opioid adaptationfollowing long-term exposure. In so-called cyclic AMP hypothesis in mid-1970s, adapted loss of opioid-mediated inhibition of cyclic AMP productionand abrupt increase in this level following opioid withdrawal were proposed asmechanistic models for opioid tolerance and dependence, respectively (1-3). Inthe current cellular models, it is well documented that the molecular eventsunderlying the reduction of opioid receptor function following morphine pre-treatments are closely correlated with receptor trafficking, including(i) phosphorylation, (ii) internalization/endocytosis, (iii) sequestration/recycling,or (iv) downregulation/breakdown of these receptors (4-8). Among these steps,the phosphorylation of opioid receptors is the most important step for desensi-tization. The direct evidence that opioid receptor function is lost by phosphor-ylation has been first reported in the studies using partially purified m-opioid receptors (MOPs) and purified cAMP-dependent protein kinase (PKA) (9-11). Itis accepted that longer exposure to opioids leads to phosphorylation of theC-terminal region of opioid receptors, followed by desensitization (12,13).However, there are reports that opioid receptors are phosphorylated by manydifferent kinases, and details of the proposed opioid receptor phosphorylationand trafficking machineries underlying opioid tolerance and desensitization havebeen described elsewhere (9,14-21).