Bl. Carter et St. Tiffany, CROSS-TOLERANCE OF ASSOCIATIVE AND NONASSOCIATIVE MORPHINE-TOLERANCE IN THE RAT WITH MU-SPECIFIC AND KAPPA-SPECIFIC OPIOIDS, Psychopharmacology, 123(3), 1996, pp. 289-296
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.