Effect of chronic administration of L-arginine, NG-nitro-L-arginine or their combination on morphine concentration in peripheral tissues and urine of the mouse.

1. Chronic administration of L-arginine (200 mg/kg, i.p) twice a day for 4 days decreased the antinociceptive response to subcutaneously, but not to intracerebroventricularly, administered morphine in male Swiss-Webster mice, as measured by the tail-flick test. 2. The decreased antinociceptive response to morphine was reversed by concurrent administration of NG-nitro-L-arginine (L-NNA) (5 mg/kg, IP), an inhibitor of nitric oxide synthase. 3. The concentrations of morphine in mice treated chronically with L-arginine and then given morphine (10 mg/kg, SC) were determined in the peripheral tissues. L-Arginine treatment significantly increased the concentration of morphine in spleen and lungs, did not modify it in liver, kidneys and urine. L-NNA by itself had no effect on the distribution of morphine in peripheral tissues but reversed the changes induced by chronic treatment with L-arginine. 4. Acute administration of L-arginine (200 mg/kg, IP) did not modify either the morphine antinociception or the morphine distribution in peripheral tissues. 5. Previous studies from this laboratory indicated that chronic treatment with L-arginine decreases the concentration of morphine in several brain regions and spinal cord of mice. 6. The facts that chronic treatment with L-arginine does not alter antinociception induced by ICV administered morphine and it increases the concentration of morphine in peripheral tissues while decreasing it in brain regions after peripheral administration of morphine suggest that the decreased antinociception induced by subcutaneously administered morphine may be related to its decreased entry into the brain.