Gavril W Pasternak MD PhD and Yuri Kolesnikov MD PhD


Despite their widespread use in the management of pain, opioids have a number of issues that limit their overall utility. Chronic use of opioids is associated with a progressive decline in their analgesic efficacy, an effect commonly termed tolerance. Although analgesic responses can usually be regained with escalation of the dose, the therapeutic index of these drugs decreases with tolerance because tolerance develops to various opioid actions at different rates, making the clinical management of patients more difficult. Thus, understanding the ways in which tolerance can either be eliminated or diminished would be a significant advantage in the therapeutic use of these agents.


A number of years ago, several laboratories reported that opioid tolerance could be impeded by the blockade of V-methyl-d-aspartate (NMDA) receptors (1,2), findings that were quickly confirmed by a large number of laboratories (3-8). In brief, the blockade of NMDA receptors prevents tolerance without interfering with opioid analgesia. This is a remarkable observation because it clearly dissociates the mechanisms responsible for the two. A wide range of NMDA antagonists are effective, including those that are both competitive and noncompetitive and even agents working on the glycine regulatory site. In general, we have found marked similarities between ^ and 8 systems, with 8 tolerance showing the same reversal with NMDA (4,8-11).

V-Methyl-d-aspartate receptors are closely associated with nitric oxide synthase (NOS) (12,13), leading to the question of whether nitric oxide (NO) also is involved in modulation of opioid tolerance. Shortly after the initial reports with NMDA antagonists, we explored the involvement of nitric oxide using inhibitors of the enzyme nitric oxide synthase (NOS), including VG-nitroarginine (NOArg). Whereas the response to a fixed morphine dose alone progressively declined and was not observed after 5 d, coadministration of NOArg maintained significant analgesia for 4 wk (Fig. 1). Chronic administration of morphine alone in this paradigm led to a twofold shift of the dose-response curve by 5 d (Table 1). Even though we did not see any analgesia at this morphine dose after 5 d, continued administration of morphine increased the levels of tolerance even further, as shown by the progressive increase in the median effective dose (ED50)) values at 10 and 28 d to fourfold and eightfold, respectively (Table 1). Yet, after 10 d of morphine coadministered with NOArg, the ED50 value was virtually the same as in naive mice. Tolerance to either the k1 drug U50, 488H or the k3 agent naloxone ben-zoylhydrazone (NalBzoH) were not affected by NOArg in this paradigm, implying that k tolerance

From: Contemporary Clinical Neuroscience: Glutamate and Addiction Edited by: Barbara H. Herman et al. © Humana Press Inc., Totowa, NJ

Fig. 1. Effect of NOArg on morphine analgesia. Mice received morphine (5 mg/kg, sc) alone or in combination with NOArg. (2 mg/kg, sc) once daily. By d 10, the morphine-alone group differed significantly from the morphine + NOArg group (p < 0.001). (Data from ref. 14).

Table 1

Effects of Modulators of NOS on Morphine Analgesia

Morphine ED50 value (mg/Kg, sc)


Without NOArg

With NOArg


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