Unsignaled morphine delivery does not disrupt the development of associative morphine tolerance in the rat

When morphine administration is paired with a distinctive context, tolerance to morphine's analgesic effects comes readily under the associative control of the drug-paired context. These associative tolerance effects are eliminated when a relatively short (i.e., 6 h) interdose interval (IDI) is used for conditioning. Contemporary models of learned tolerance explain the absence of learning at short IDIs by positing that residual morphine effects from a recent drug exposure disrupt the formation of drug-context associations. The present studies examined the impact of unsignaled morphine injections given 6 h prior to drug-context pairings on the development of associative tolerance. Analgesia was measured by the tail-flick method, and tolerance levels were assessed by dose response curve methodology. Morphine preexposure had no detectable influence on the acquisition of associative tolerance when rats were tested immediately after conditioning, after a 30- day rest interval, or after a 30-day period of daily saline injections in their home cage environment. These data suggest disruption of associative tolerance effects at short IDIs is not attributable to residual effects of morphine from the immediately preceding trial.