Nmda Receptors And The Development Of Opiate Physical Dependence

At the same time that we first reported that MK-801 inhibited tolerance to morphine analgesia, we reported that this drug also inhibited physical dependence on morphine (25). The effects were identical to those on tolerance in that MK-801 inhibited the development but not the expression of physical dependence. In other words, MK-801 inhibited withdrawal-related behaviors when administered with morphine during the acquisition of physical dependence; but the drug did not affect these behaviors when administered immediately prior to naloxone-precipitated withdrawal. A similar inhibition of the development of physical dependence by NMDA receptor antagonists has been observed more recently by others using a variety of NMDA receptor antagonists and a variety of behavioral measures of withdrawal (Table 5).

One of the most intriguing recent findings relevant to this topic is that of Zhu et al. (108), demonstrating that treatment with antisense oligonucleotides directed against the NMDA receptor (NMDA-R1 subunit) can inhibit the development of opiate physical dependence. Intraventricular administration of antisense oligonucleotides, but not sense (control) oligonucleotides, decreased levels of brain NMDA receptors and inhibited the development of morphine physical dependence, as assessed by several different behavioral signs of withdrawal. This finding together with the pharmacological results provide strong evidence that activation of NMDA receptors is necessary for the normal development of opiate physical dependence.

The opitate-withdrawal syndrome is a complex phenomenon, characterized by several different signs and symptoms. It is presently unclear if NMDA receptor antagonists inhibit the development of the syndrome as a whole or a subset of signs and symptoms. Given the variety of physiological and behavioral effects expressed during withdrawal and their mediation by different physiological systems, it would be surprising if the development of all of these would be inhibited by NMDA receptor antagonists. Thus far, different studies have explored different signs and symptoms and utilized different methods of quantification. It is therefore difficult to make comparisons across experiments. NMDA receptor antagonists have been reported to interfere with "active" signs such as jumping, wet-dog shakes, and teeth chattering, "passive" signs such as diarrhea, weight loss, and piloerection, and "emotional" symptoms such as vocalizations and irritability (see Table 5). It will be useful to clarify the effects of NMDA receptor antagonists on these effects, both individually and collectively, in order to better understand the potential role of NMDA receptors in the development of these different signs and symptoms and their relationships to one another.

Although the effects of NMDA receptor antagonists on the development of physical dependence are relatively clear, the effects of these drugs on the expression of withdrawal are more problematic. Several groups have reported that NMDA receptor antagonists will inhibit the expression of opiate physical dependence (45,109-123). However, this may be a nonspecific effect related to behavioral competition rather than a specific blockade of the neural processes responsible for opiate withdrawal (2,124,125). An important clue to this possibility is found in the doses required to inhibit the development of physical dependence relative to those necessary to inhibit the expression of withdrawal. As we have discussed previously (2,125,126), doses required to inhibit the expression of opiate withdrawal are typically greater than those necessary to inhibit the development of physical dependence. Recent studies reinforce this idea. Gonzalez and co-workers (45), for example, found that doses of MK-801 necessary to inhibit the expression of withdrawal were considerably greater than those necessary to inhibit the development of physical dependence. Because doses of NMDA receptor antagonists required to inhibit the expression of opiate physical dependence are often high enough to produce significant locomotor effects, it has been suggested that these drugs may nonspecifically interfere with the expression of the opiate-withdrawal syndrome (2,125,126). On the other hand, some studies have shown inhibition of the expression of certain aspects of withdrawal at relatively low doses of NMDA receptor antagonists (45,114,118-120). It may be that NMDA receptors have a role not only in the development of opiate physical dependence but also in certain aspects of the expression of withdrawal. Future studies should focus on low doses of NMDA receptor antagonists, comparing their effects on the development versus the expression of opiate physical dependence, in order to help clarify this issue.

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