CROSS-TOLERANCE OF ASSOCIATIVE AND NONASSOCIATIVE MORPHINE-TOLERANCE IN THE RAT WITH MU-SPECIFIC AND KAPPA-SPECIFIC OPIOIDS

The present study examined the cross-tolerance profiles of associative ly 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 inj ections either paired or unpaired with a distinctive environment and t hen tested for tolerance using the tail-flick method. Evidence was fou nd that nonassociative morphine tolerance, which was produced using a 6-h interdose interval (IDI), was receptor-specific, i.e. cross-tolera nt with analgesia produced by mu-specific, but not kappa-specific drug s. Nonassociative tolerance was characterized by a shift to the right in dose-response curves of 0.32 log units in morphine-tested animals a nd 0.28 log units in fentanyl-tested animals. Conversely, associative morphine tolerance, which was produced using a 96-h IDI, evidenced a l ack of receptor specificity by showing cross-tolerance to the analgesi c effects of U50,488H. Associative tolerance was characterized by shif ts of 0.42 log units in morphine-tested animals, 0.34 log units in fen tanyl-tested animals, and 0.39 log units in U50,488H-tested animals. T hese 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 tole rance that assume a unitary set of mechanisms subserving associative a nd nonassociative tolerance.