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.