Opioid-NMDA receptor interactions may clarify conditioned (associative) components of opioid analgesic tolerance

Recent evidence suggests that acute administration of opioid analgesic drug s (such as morphine or heroin) produces delayed hyperalgesia. This hyperalg esic response is likely to result from hyperactivation of NMDA receptors tr iggered by stimulation of opioid receptors and may mediate acute tolerance. In support of this hypothesis, blockade of NMDA receptors attenuates opioi d-induced delayed hyperalgesia and prolongs the duration of antinociceptive activity of morphine. Furthermore, the NMDA receptor-induced hyperalgesia is likely an unconditioned response to opioid receptor stimulation that bec omes spatiotemporally associated with environmental cues accompanying repea ted opioid exposure. This hypothesis conforms to the traditional Pavlovian requirement for conditioned and unconditioned responses to be qualitatively similar. In support of the role of NMDA receptor hyperactivation in morphi ne tolerance, NMDA receptor antagonists have been shown to block developmen t of analgesic tolerance induced by repeated exposures to morphine. The vie w of the conditioned nature of opioid tolerance may be significantly extend ed by assuming that upon repeated drug administration an early-onset effect of a drug may become a predictive stimulus for a later-onset effect and, c onsequentially, it may become empowered to elicit the later-onset effect it self. Such 'intradrug' conditioning hypothesis is well in line with the cur rent experimental evidence but further studies will be needed to verify it directly. (C) 2001 Published by Elsevier Science Ltd.