Nmda Receptors And The Development Of Opiate Sensitization

Wolf and co-workers were the first to report on the ability of NMDA receptor antagonists to inhibit opiate sensitization (74,95). These investigators noted that both MK-801 and the competitive NMDA receptor antagonist CGS 19755, at relatively low and selective doses, inhibited the development of sensitization to the locomotor-stimulant effect of morphine. The pattern observed was strikingly similar to that seen with morphine tolerance, in that the antagonists inhibited the development but not the expression of morphine sensitization (Table 4).

Recent research from others appears to present a more complicated picture. Vanderschuren et al. (98), for example, reported that only high doses of MK-801, which produced considerable lethality in combination with morphine, had the ability to inhibit sensitization to the locomotor-stimulant effect of morphine in rats. Lower doses, which did not produce lethality, did not affect sensitization. These authors therefore suggest that the effect may be a nonspecific drug interaction, rather than an inhibition of neural and behavioral plasticity.

Iijima and co-workers (97), in studies on mice, also reported that high doses of MK-801 were necessary to inhibit morphine sensitization. Although lethality was not seen in this study, the doses of MK-801 required to inhibit sensitization were very high and produced significant locomotor stimulation on their own. It should be noted that the locomotor effects of morphine in mice are quite different than those in rats. Whereas high doses of morphine in rats produce a biphasic locomotor response, with an initial locomotor depression followed by locomotor stimulation, this drug in mice produces dose-dependent stimulation of locomotion without the locomotor depression. The effects in mice may, therefore, be difficult to directly compare to those in rats.

In exploring an alternative behavior in rats, stereotyped biting, Livezey et al. (96) reported that a high dose of MK-801 inhibited both the development and expression of sensitization to this effect. Lower doses of MK-801 were not examined in this experiment so it is not clear if the high dose was required.

As mentioned earlier, we have begun studies exploring the role of NMDA receptors in tolerance and sensitization to the locomotor effects of morphine. In these studies, we observed that MK-801, at a relatively low and selective dose, inhibited the development but not the expression of sensitization to the locomotor-stimulant effect of morphine (76,86). Adding strength to this finding, this inhibition paralleled inhibition of tolerance to the locomotor-depressant effect and tolerance to the analgesic effect of morphine in the same experimental animals. In more recent experiments, we found that the low-affinity noncompetitive NMDA receptor antagonist memantine also inhibited sensitization to the loco-motor-stimulant effect of morphine (Peterson and Trujillo, unpublished observations). Results from our laboratory therefore support the findings of Wolf and co-workers that the development of opiate sensitization is inhibited by low selective doses of NMDA receptor antagonists.

Taken together, there appears to be general agreement that NMDA receptor antagonists inhibit the development of morphine sensitization; however, there is disagreement about the doses necessary to achieve this effect. At first glance, it is unclear why some studies report inhibition of this effect at low doses of NMDA receptor antagonists, whereas others require higher doses. However, Wolf (6) has suggested a potential resolution to this discrepancy. She suggested that context-dependent (or associative) sensitization may be less sensitive to inhibition by NMDA receptor antagonists than context-independent (or nonassociative) sensitization. Context-dependent sensitization arises when a drug is administered repeatedly in the same environment and the effects of the drug become intimately associated with environmental cues. This form of sensitization requires learning and is expressed only in the presence of the environmental cues in which drug administration occurred. In contrast, context-independent sensitization arises in the absence of environmental cues, does not involve learned associations between drug effects and environmental cues, and is, therefore, a more direct form of sensitization. If Wolf is correct, then this may help to explain why some studies find inhibition of morphine sensitiza-tion at relatively low doses, whereas others require higher doses—those that required high doses may have examined context-dependent sensitization, rather than context-independent sensitization. The studies in our laboratory were performed in a manner that promoted the development of context-independent sensitization, which may explain why lower doses were able to inhibit this phenomenon.

Although the results on sensitization are less clear than those on opiate tolerance, it appears that most investigators agree that sensitization to the locomotor-stimulant effect of morphine is inhibited by NMDA receptor antagonists, albeit at different doses and with different interpretations of the results. Taken together, we believe the data offers tentative support of a role for NMDA receptors in the development of opiate sensitization. Further studies should help to resolve this issue. As mentioned earlier in the discussion on tolerance, studies should be designed to facilitate comparisons with other behaviors and other forms of opiate-induced neural and behavioral plasticity.

It should be added that NMDA receptor antagonists have been found to inhibit the development of sensitization to the stimulant effects of several other drugs of abuse, including amphetamine, cocaine, and nicotine (see refs. 2,6,99, and 100, for review). These findings are very intriguing, suggesting that NMDA receptors may be involved in sensitization to a variety of different drugs of abuse. Understanding the mechanisms underlying sensitization is of particular interest to the field of substance abuse because this process may be involved in the craving that arises from repeated drug use (5,6).

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