Associative and non-associative fentanyl tolerance in the rat: evaluation of cross tolerance with mu-and kappa-specific opioids

Rationale: Associative tolerance to the analgesic effects of morphine is mo st pronounced when morphine is paired with a distinctive context at a long interdose interval (IDI). In contrast, morphine administered at a short IDI promotes the development of non-associative tolerance and disrupts the acq uisition of associative tolerance. The impact of LDI an the development of associative tolerance to opioids other than morphine has not been investiga ted previously. Objectives: This research examined associative and non-asso ciative tolerance to the analgesic effects of fentanyl in rats. Cross toler ance for these two forms of tolerance with morphine (mu-receptor agonist) a nd U50,488H (kappa-receptor agonist) analgesia was also investigated. Metho ds: Animals were given eight fentanyl injections (0.10 mg/kg) paired or unp aired with a distinctive context at either a 3-h (short) or 96-h (long) IDI . Subjects were then tested for tolerance in the distinctive context using the tail-flick procedure and dose-response curve methodology. Results: At t he short IDI, animals eveloped non-associative tolerance to fentanyl that w as receptor specific, i.e., cross tolerant with morphine analgesia but not with U50.488H analgesia. At the long LDI, fentanyl-tested animals displayed tolerance that appeared to be controlled primarily by associative processe s. This associative form of tolerance was also receptor specific, displayin g cross tolerance with morphine but not with U50,388H. Conclusions: The imp act of IDI on the development of non-associative and associative fentanyl t olerance is consistent with findings obtained with morphine showing that co nditions conducive to the development of non-associative tolerance disrupt the acquisition of associative tolerance. The cross-tolerance data, however , did not parallel previous research examining the cross-tolerance profiles of associative and non-associative morphine tolerance.