8.1. Potential Alternative Explanations
The hypothesis that led to studies in this area is relatively simple and straightforward: Because NMDA receptors are involved in many forms of neural and behavioral plasticity, these receptors may also be involved in the neural and behavioral plasticity arising from long-term administration of drugs of abuse. As discussed earlier, studies on the development of opiate tolerance, sensitization, and physical dependence are consistent with this hypothesis. However, there have been suggestions that the ability of NMDA receptor antagonists to inhibit the development of these phenomena may be due to other factors. Three of the most popular alternative explanations are drug side effects, inhibition of associative learning, and state dependency (70). Although these factors may indeed contribute to some of the results obtained in this area, the abundance of evidence suggests that they are not responsible for the majority of results (see ref. 70 for detailed discussion). Perhaps some of the most powerful evidence that these factors are not responsible is that inhibition of opiate-induced neural and behavioral plasticity is obtained with a variety of different NMDA receptor antagonists, with different behavioral and interoceptive effects, and typically at doses that produce few significant effects on ongoing behavior (see Tables 1-6 and ref. 70). Moreover, similar effects are obtained across different forms of plasticity, sometimes in the same experimental animals. These observations, together with others, suggest that the most parsimonious explanation for the results is that NMDA receptors are involved in the neural changes that underly the development of tolerance, sensitization, and physical dependence to several different effects of opiates (70).
Because of its widespread clinical use, its long history in psychopharmacological research, and its relative selectivity for ^-opiate receptors, morphine is the prototypical ^-opiate agonist, and is, therefore, used as the drug of choice when examining ^-opioid receptor function. This has been the case in the study of the role of NMDA receptors in opiate-induced neural and behavioral plasticity. It has been assumed, based on studies with morphine, that NMDA receptor antagonists would inhibit tolerance, sensitization, and physical dependence to other ^ agonists in a similar manner. However, Bilsky and co-workers (39) have obtained evidence that tolerance to ^ agonists other than morphine may not be affected by NMDA receptor antagonists. In studies on tolerance to opiate analgesia in mice, these authors reported that whereas MK-801 and the competitive NMDA receptor antagonist LY235959 inhibited development of tolerance to morphine, these drugs did not affect tolerance to the peptide ^ agonists DAMGO and PL017 and the nonpeptide opioid fentanyl. It is possible, as suggested by the authors (39) that the development of tolerance to ^ agonists that are more selective and/or more efficacious than morphine involves mechanisms that are independent of NMDA receptors. However, more recent studies question these findings. Mao et al. (51), for example, demonstrated that MK-801 can, indeed, inhibit the development of tolerance to the analgesic effect of the peptide ^ agonist DAMGO, as well as the development of physical dependence as measured by hyperalgesia (this study used a different experimental approach than the Bilsky et al. study, which may help to explain the contrasting findings). Allen and Dykstra (65) have suggested that the ineffectiveness of the NMDA receptor antagonists in the Bilsky et al. study may be related to differences in the magnitude of tolerance produced by the different opioids. In studies on morphine tolerance in rats, Allen and Dykstra found that higher levels of tolerance produced by higher doses of morphine were more resistant to NMDA receptor inhibition than lower levels of tolerance. Thus, NMDA receptors may, indeed, be involved in opiate-induced neural and behavioral plasticity produced by a variety of ^ agonists, but the involve ment of NMDA receptors may diminish at higher levels of tolerance. As the magnitude of tolerance increases, other neural mechanisms, such as changes in receptor number, may contribute to the development of this phenomenon.
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