On the basis of a conditioning analysis of drug tolerance, drug-associated cues become associated with the drug effect. These cues elicit conditional compensatory responses and modulate the expression of tolerance. Although there are many findings consistent with the conditioning analysis of tolerance, there also are contrary findings. The results of these experiments suggest that some of the apparently contradictory findings result because interoceptive pharmacological cues, as well as exteroceptive environmental cues, are paired with a drug effect. That is, within each administration, early drug-onset cues may become associated with the later, larger drug effect, and these pharmacological cues may overshadow simultaneously present environmental cues. We demonstrate the contribution of such intraadministration associations to tolerance to the analgesic effect of morphine and to the expression of conditional compensatory hyperalgesia.

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