Info

a Noncomp = noncompetitive antagonist; comp = competitive antagonist; glycine = glycine-site antagonist; polyamine = polyamine-site antagonist.

b Although the Tzschentke and Schmidt (75) study purportedly examined sensitization, this is an apparent misinterpretation. As discussed previously (70), the effects observed appeared to be tolerance to the locomotor-depressant effect of morphine, rather than sensitization to the locomotor-stimulant effect.

a Noncomp = noncompetitive antagonist; comp = competitive antagonist; glycine = glycine-site antagonist; polyamine = polyamine-site antagonist.

b Although the Tzschentke and Schmidt (75) study purportedly examined sensitization, this is an apparent misinterpretation. As discussed previously (70), the effects observed appeared to be tolerance to the locomotor-depressant effect of morphine, rather than sensitization to the locomotor-stimulant effect.

locomotion seen in the first 1-2 h after administration, followed by stimulation of locomotor activity over the next 2-3 h (76,78-85). With repeated administration, tolerance develops to the locomotor depression, and sensitization to the locomotor stimulation (70,76,78-83,85).

In early studies on the effects of NMDA receptor antagonists on tolerance to opiate analgesia, we reported anecdotal evidence that these drugs may inhibit tolerance to the locomotor depressant effect of morphine. Although not systematically quantified, qualitative assessment of the animals suggested that morphine-induced locomotor depression persisted longer in animals that received coadministration of morphine with NMDA receptor antagonists (36). This observation was confirmed by Jeziorski et al. (74), who reported that MK-801 and the competitive NMDA receptor antagonist CGS 19755 inhibited the development of tolerance to the locomotor-depressant effect of morphine. On the other hand, a more recent study by Tzschentke and Schmidt (75) suggests that MK-801 does not inhibit tolerance to the locomotor-depressant effect of morphine. It should be noted that this latter study utilized a complicated experimental design that may have interfered with the ability to detect certain drug effects (see ref. 70 for a more detailed discussion). Thus, published studies to date appear to conflict on whether or not NMDA receptors are involved in the development of tolerance to morphine-induced locomotor depression.

We have recently begun studies to address this question and more thoroughly explore the potential role of NMDA receptors in tolerance to the locomotor depressant effect of opiates. In the first series of studies, we examined the effects of MK-801 on three different forms of opiate-induced behavioral plasticity, all in the same animals: tolerance to the locomotor-depressant effect of morphine, tolerance to morphine-induced analgesia, and sensitization to the locomotor-stimulant effect of morphine (76,86). In these studies, MK-801 inhibited the development, but not the expression of all three phenomena. Moreover, very recent experiments suggest that the low-affinity noncompeti-tive NMDA receptor antagonist memantine also inhibits tolerance to the locomotor-depressant effect of morphine (Peterson and Trujillo, unpublished observations). Taken together, we believe the data support a role for NMDA receptors in the development of tolerance to the locomotor-depressant effect of opiates.

4.3. Suppression of Operant Responding

Another robust effect of opiates, when administered acutely, is the ability to suppress operant responding. This effect is likely related to opiate-induced locomotor depression, discussed above— opiates produce suppression of a variety of behaviors, including locomotor activity and operant responding, when administered acutely in high doses. Recently, Bespalov and co-workers (77) obtained evidence that NMDA receptor antagonists inhibit the development of tolerance to morphine-induced suppression of operant responding. Although the study was designed to explore the development of tolerance to the discriminitive stimulus effects of morphine, the investigators noted a potent reduction in the rate of responding with morphine and the development of tolerance to this effect. Each of the NMDA receptor antagonists used in this experiment (a noncompetitive antagonist, a competitive antagonist, a glycine-site antagonist, and a polyamine-site antagonist) inhibited tolerance to morphine-induced suppression of operant responding. The fact that drugs acting on all four sites on the NMDA receptor complex produced similar effects provides a powerful demonstration of the potential role of NMDA receptors in this phenomenon. Although a different behavioral end point was used than typically seen in studies of locomotor depression, we believe that these results are consistent with the idea that NMDA receptors are involved in tolerance to the locomotor-depressant effects of opiates. Alternatively, these results may suggest involvement of NMDA receptors in the development of tolerance to yet another opiate-induced behavior.

4.4. Discriminitive Stimulus Effects

As noted above, Bespalov and co-workers (77) explored the potential role of NMDA receptors in tolerance to the discriminitive stimulus effects of morphine. In this study, morphine produced a potent stimulus effect, and tolerance developed to this effect with repeated administration. Interestingly, the development of tolerance to the stimulus effect of morphine was inhibited by the competitive antagonist D-CPPene and the polyamine-site antagonist eliprodil, but not by MK-801 or the glycine-site partial agonist (+)-HA-966. Although it is nuclear why differences were seen across these compounds, the results offer intriguing preliminary evidence that NMDA receptors may be involved in tolerance to the discriminitive stimulus effects of opiates.

4.5. Summary

It is striking that NMDA receptor antagonists have the ability to inhibit tolerance to a variety of different opiate effects, including analgesia, locomotor depression, suppression of operant responding, and discriminitive stimulus effects. These results suggest that NMDA receptors may have a widespread role in the development of opiate tolerance. This role, however, is apparently not universal, as MK-801 did not inhibit the development of tolerance to morphine-induced hyperthermia. In a similar demonstration, Rauhala and co-workers (87) reported that the nitric oxide synthesis inhibitor N-nitro-l-arginine inhibited tolerance to the analgesic effect of morphine, but not the hormonal effects. These results raise the intriguing but not surprising possibility that NMDA receptors are involved in some forms of opiate-induced neural and behavioral plasticity, but not others. Opiate tolerance is not a singular phenomenon. Tolerance to different effects of opiates differs across a variety of parameters, including the time-course of development, threshold doses, degree of tolerance, and disappearance (77,83,88-90). Additionally, the development of tolerance to different opiate effects involves different neural systems and likely involves different cellular events (3,91-94).

As research progresses on the potential role of NMDA receptors in tolerance to different effects of opiates, studies should be designed in a manner to allow comparisons to be made both within and across experiments. Dose responses should be explored and different antagonists should be utilized before it is concluded that NMDA receptors are or are not involved in a particular effect. The most powerful data will come from those studies in which the effects of NMDA receptor antagonists are

Table 4

Inhibition of the Development of Opiate Sensitization by NMDA Receptor Antagonists

Table 4

Inhibition of the Development of Opiate Sensitization by NMDA Receptor Antagonists

NMDA receptor

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