N-nitro-L-arginine attenuates development of tolerance to antinociceptive but not to hormonal effects of morphine.

The effect of N-nitro-L-arginine methyl ester on thyrotropin (TSH), growth hormone (GH) and prolactin levels in serum was studied after a single dose in male rats. The effect of repeated N-nitro-L-arginine methyl ester on the development of tolerance to the multiple effects of morphine was also examined. N-Nitro-L-arginine methyl ester (25 mg/kg i.p.) decreased cold-stimulated (rats were kept 30 min at +4 degrees C) TSH levels but did not alter basal TSH, GH or prolactin levels. Acute or repeated N-nitro-L-arginine methyl ester treatments were not antinociceptive alone, neither did they modify the effect of acute morphine. A 5-day treatment with increasing doses of morphine induced antinociceptive tolerance. This was attenuated by N-nitro-L-arginine methyl ester co-administration on the 3rd day, less so on the 5th day. Repeated morphine produced tolerance to the effect on TSH (decrease) and prolactin (increase) levels, but sensitization to the GH-elevating effect, measured after a 4-day delay. A 5-day treatment with N-nitro-L-arginine methyl ester did not modify the development of tolerance to the hormonal effects of morphine. In the case of TSH, it is difficult to draw a conclusion because the 5-day N-nitro-L-arginine methyl ester and morphine treatment generally decreased basal TSH levels. Sensitization to the hyperthermic effect of morphine occurred after a 4-day delay and this was not altered by N-nitro-L-arginine methyl ester. These results suggest that both nitric oxide-dependent and independent mechanisms are involved in the development of tolerance to the various effects of morphine.