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

Abstract

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.

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

“…In contrast, rats given morphine at the short IDI developed substantial non-associative tolerance; this tolerance displayed no contextual specificity and decayed completely at the 30-day retention test. These results were in line with other research showing that conditions supporting the development of one form of tolerance (associative or non-associative) interfered with the development of the other form (Dafters et al 1988;Tiffany and Maude-Griffin 1988;Dafters and Odber 1989;Carter and Tiffany 1996;Cox and Tiffany 1997).…”

“…The degree of cross tolerance between opioids is generally believed to depend on the extent to which the drugs' effects are controlled by common receptor mechanisms. For example, rats tolerant to the analgesic effects of morphine display cross tolerance to analgesia produced by fentanyl (Carter and Tiffany 1996), an opioid that, like morphine, produces effects mediated predominantly by mu-opioid receptors (Maguire et al 1992). In contrast, morphine tolerance may not generalize to the analgesic actions of the opioid U50,488H, a highly selective kappa-receptor agonist with little affinity for mu receptors (Bhargava et al 1989;Carter and Tiffany 1996).…”

“…This research investigated the generality of the influence of IDI manipulations on associative and non-associative tolerance that have been established with morphine (Tiffany and Maude-Griffin 1988;Tiffany et al 1992;Carter and Tiffany 1996;Cox and Tiffany 1997). Furthermore, this research explored whether the profile of cross-tolerance effects obtained with morphine (Carter and Tiffany 1996) generalized to fentanyl.…”

“…As an illustration of the importance of distinguishing between these two types of tolerance, Carter and Tiffany (1996) found that the profiles of morphine cross tolerance with mu-and kappa-receptor agonists differed as a function of the associative or non-associative nature of the tolerance. In this research, non-associative morphine tolerance was receptor specific, displaying cross tolerance with fentanyl (mu-agonist) but not with U50,488H (kappa agonist).…”

A locus and mechanism of action for associative morphine tolerance

“…Animals that become non-associatively tolerant to morphine are selectively tolerant to other μ-opioid receptor agonists. In contrast, associative morphine tolerance generalizes such that the effects of agonists acting at other opioid receptors are also reduced 29 . This suggests that these two types of morphine tolerance involve different CNS circuitry.…”