Opioid tolerance and neuroplasticity.

Opioid analgesics are highly effective for treating many forms of acute and chronic pain. The development of opioid analgesic tolerance is a pharmacological phenomenon indicative of the cellular and system adaptation that could affect the clinical use of opioid analgesics. Activation of N-methyl-D-aspartate receptors and protein kinase C as well as regulation of glutamate transporters has been implicated in the mechanisms of opioid tolerance, suggesting a possible link between neural plasticity and the mechanisms of opioid tolerance. More recent studies have shown that neural plasticity associated with the development of opioid tolerance may activate a pronociceptive mechanism within the central nervous system that could counteract the analgesic effects of opioids. Thus, exposure to opioids could lead to two seemingly unrelated cellular processes, i.e. (1) the development of opioid tolerance--a negative sign of cellular adaptation, and (2) the development of opioid-induced pain sensitivity--a positive sign of cellular adaptation. The converging effects of these cellular mechanisms would significantly reduce the opioid analgesic efficacy. The current evidence also suggests new approaches for improving the clinical use of opioid analgesics.