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5.2 (2.1,9.1) 2.7

Note: Mice were treated with either nothing (naive), NMDA (1 mg/kg for 5 d), or l-arginine (50 mg/kg, ip for 3 d) and then examined for morphine analgesia. Source: Data from ref. 26.

Note: Mice were treated with either nothing (naive), NMDA (1 mg/kg for 5 d), or l-arginine (50 mg/kg, ip for 3 d) and then examined for morphine analgesia. Source: Data from ref. 26.

Because NOS inhibitors do not distinguish between these variants, their actions reflect the blockade of both systems and the pharmacological activity is likely the result of the net difference between the two systems. Clearly, selective inhibitors of these variants would be interesting pharmacologically. A major question is whether this cascade is a therapeutic target clinically. A number of NMDA receptor antagonists have been developed, but they have not been widely used because of psychotomimetic side effects. Nitric oxide synthase inhibitors have the potential of serious vascular adverse effects. Yet, the more basic question is the overall importance of the NMDA/NOS cascade in opioid tolerance. It is important to note that most studies documenting the role of the cascade in tolerance have examined low levels of opioid tolerance. It is not entirely clear that the same mechanisms are important in more profound tolerance, as is often seen in clinical situations. Opioid tolerance is likely to involve a vast array of mechanisms, ranging from the receptor itself, to transduction systems within the cell, to circuitry. Thus, the question of the therapeutic potential of blockers of this cascade remains open. However, it is tantalizing to consider the possibility that analgesic tolerance can be prevented through inhibition of this cascade while tolerance still develops to the side effects associated with opioid use. For example, inhibition of gastrointestinal motility and respiratory depression undergo tolerance more slowing than analgesia, implying that they may involve different mechanisms of tolerance.

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