Vol. 281, Issue 2, 707-712, 1997

Mechanism of Attenuation of Morphine Antinociception by Chronic Treatment with L-Arginine¹

Hemendra N. Bhargava, Jing-Tan Bian and Shailendra Kumar

Department of Pharmaceutics and Pharmacodynamics, The University of Illinois at Chicago Health Sciences Center, Chicago, Illinois

The effects of twice-daily injections of L-arginine or D-arginine (200 mg/kg i.p.) for 4 days on morphine-induced antinociception, brain nitric oxide synthase activity and brain and serum distribution of morphine and brain µ-opioid receptors labeled with [³H][D-Ala²,MePhe⁴,Gly⁵-ol]enkephalin were determined in male Swiss-Webster mice. Chronic treatment with L-arginine, but not D-arginine, decreased the antinociceptive response to morphine in mice, increased the activity of nitric oxide synthase in the midbrain and decreased brain levels of morphine, compared with vehicle-injected controls. Significant decreases in morphine levels were observed in midbrain, pons and medulla, hippocampus, striatum and spinal cord of L-arginine-treated mice, in comparison with vehicle-injected mice. However, the levels of morphine in cortex, amygdala and hypothalamus of L-arginine- or D-arginine-treated mice did not differ from those of vehicle-injected controls. Acute treatment with L-arginine (200 mg/kg i.p.) or D-arginine (200 mg/kg i.p.) did not modify either morphine antinociception or morphine distribution in brain regions or the spinal cord. Chronic administration of L-arginine or D-arginine did not alter the B_max or K_d values of [³H][D-Ala²,MePhe⁴,Gly⁵-ol]enkephalin binding to the mouse brain membranes. These results suggest that chronic treatment with L-arginine reduces the antinociceptive effect of morphine by increasing brain nitric oxide synthase activity and by decreasing the concentration of morphine in certain brain regions and spinal cord.