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 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 mid-
1970s, 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 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). It
is accepted that longer exposure to opioids leads to phosphorylation of the
C-terminal region of opioid receptors, followed by desensitization (12,13).
However, there are reports that opioid receptors are phosphorylated by many
different kinases, and details of the proposed opioid receptor phosphorylation
and trafficking machineries underlying opioid tolerance and desensitization have
been described elsewhere (9,14-21).
