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Source: Data from refs. 14 and 15.

Source: Data from refs. 14 and 15.

involved different mechanisms. As noted earlier, 8 tolerance showed the same sensitivity to these treatments as morphine (4,8-11).

Because blockade of NOS potentiated opioid action over time, eliminating tolerance, we also explored whether the opposite was true. l-Arginine is the natural substrate for the production of NO and its administration can induce NO formation. A single dose of l-arginine lowered morphine analgesic activity, but the effect was more pronounced after l-arginine was given alone over a few days (Table 1). Coadminsitration of NOArg, however, prevented the effects of l-arginine, confirming its actions through NOS. As expected, d-arginine, which is not a substrate for NOS, was ineffective. Again, we observed differences between ^ and k systems, with k systems insensitive to these treatments.

Can tolerance be reversed once it develops? If NOArg is added to the chronic morphine treatment after tolerance is established, the animals regained their sensitivity toward morphine despite

Fig. 2. Effect of acute spinal and supraspinal NOArg on morphine analgesia. Groups of mice received the indicated dose of NOArg either spinally or supraspinally, followed by morphine (5 mg/kg, sc) 30 min later. Results are from ref. 20.)

NOArg Dose Og)

Fig. 2. Effect of acute spinal and supraspinal NOArg on morphine analgesia. Groups of mice received the indicated dose of NOArg either spinally or supraspinally, followed by morphine (5 mg/kg, sc) 30 min later. Results are from ref. 20.)

its continued administration. Thus, the blockade of NOS receptor blockade restored analgesic sensitivity in morphine-tolerant animals. In addition to opening a novel therapeutic approach toward ameliorating tolerance, these observations also have implications with regard to the mechanism of tolerance. It suggests that tolerance is not a static state, but rather a dynamic one balancing factors that are inducing it and others acting to restore analgesic sensitivity.

Physical dependence has long been associated with tolerance, although there are suggestions that their mechanisms may differ (16,17). NOArg also attenuated signs of morphine dependence in mice, although higher doses of drug seemed to be needed (14). Others reported similar findings (18,19).

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