Spontaneous recovery of tolerance to the analgesic effect of morphine.

There is now substantial evidence that associative processes contribute to the development and expression of narcotic tolerance. Like other conditioned responses, the compensatory response (CR) thought to mediate tolerance can be extinguished by repeatedly presenting the conditioned stimulus (CS, drug-paired contextual cues) alone. In the present experiments, rats were used to determine if conditioned tolerance to the analgesic effect of morphine would spontaneously recover following a sufficient delay between the last extinction trial and reexposure to the CS. It was found that tolerance spontaneously recovered 72, but not 24 h following the last of nine extinction trials. As well as providing support for a Pavlovian model of narcotic tolerance, this finding has important clinical implications for cue-exposure drug and alcohol rehabilitation strategies.