Cross-tolerance of associative and nonassociative morphine tolerance in the rat with mu- and kappa-specific opioids

The present study examined the cross-tolerance profiles of associatively and nonassociatively morphine-tolerant rats with analgesia produced by morphine and fentanyl (mu-receptor agonists) and U50,488H (a kappa-receptor agonist). Subjects were given a series of eight morphine injections either paired or unpaired with a distinctive environment and then tested for tolerance using the tail-flick method. Evidence was found that nonassociative morphine tolerance, which was produced using a 6-h interdose interval (IDI), was receptor-specific, i.e. cross-tolerant with analgesia produced by mu-specific, but not kappa-specific drugs. Nonassociative tolerance was characterized by a shift to the right in dose-response curves of 0.32 log units in morphine-tested animals and 0.28 log units in fentanyl-tested animals. Conversely, associative morphine tolerance, which was produced using a 96-h IDI, evidenced a lack of receptor specificity by showing cross-tolerance to the analgesic effects of U50,488H. Associative tolerance was characterized by shifts of 0.42 log units in morphine-tested animals, 0.34 log units in fentanyl-tested animals, and 0.39 log units in U50,488H-tested animals. These results were interpreted as suggesting the mechanisms responsible for associative tolerance differ from those producing nonassociative tolerance. This conclusion is problematic for theories of learned tolerance that assume a unitary set of mechanisms subserving associative and nonassociative tolerance.