[Complexity and physiology of the analgesic effects of opioids]

Nowadays, it is considered that clinical pain is not only a reflexion of the nociceptive stimulus intensity, but is to a large extent the expression of neural plasticity including both peripheral and central sensitization. N-Methyl-D-aspartate receptors (NMDA-Rs) play a critical role in the central pain sensitization process leading to exaggerated pain and chronic pain. Although opioids are unsurpassed analgesics, we observed that opioids induced delayed and sustained NMDA-related hyperalgesia after an initial analgesia suggesting a pain sensibilisation process. It is shown that NMDA receptor antagonists and specific diets able to negatively modulate NR2B subunit containing NMDA receptors prevented abnormal pain hypersensitivity, partially reversed chronic pain and restored the opioid effectiveness on opioid-resistant pain models.