The roles of pain facilitatory systems in opioid tolerance

Opioids are powerful analgesic agents and have been widely used in clinical pain management for decades. Nevertheless, both acute and chronic opioids administration may produce tolerance, as indicated by a lowered responsiveness to the drugs at a later time. Koob and Bloom described two possible mechanisms of drug tolerance: a within-system and a between-systems adaptation. Opioid receptors uncoupling from G-proteins and receptor down-regulation, in particular the receptor's high affinity sites, are well-known mechanisms (the within-system) of opioid tolerance. A series of recent studies have proposed that a between-systems, particularly the pain facilitatory systems (opiate-activated opponent systems), may also involve in the development of opioid tolerance. Several lines of evidence suggest that N-methyl-D-asparate (NMDA) receptors activation and the subsequent nitric oxide (NO) production probably play a between-systems mechanism of opioid tolerance. Recently, our and others' studies also found that cyclooxygenase (COX) inhibitors could attenuate the opioid tolerance without enhancing morphine's antinociceptive effect. Taking all these findings together, the pain facilitatory systems included the NMDA-receptors, NO, and COX systems may also play important roles in opioid tolerance. In summary, except the opioid receptor uncoupling and opioid receptor down-regulation, chronic morphine treatment may also activate pain facilitatory systems (NMDA receptor activation, NO production, and COX ac-tivation) during opioid tolerance development. It implies that some complicated interactions may happen among the opioid receptor, NMDA-receptor, NO, and COX systems and are worth further investigations.