EFFECT OF CHRONIC ADMINISTRATION OF L-ARGININE, N-G-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, IP) twice a day fo r 4 days de creased the antinociceptive response to subcutaneously, bu t not to intracerebroventricularly, administered morphine in male Swis s-Webster mice, as measured by the tail-flick test. 2. The decreased a ntinociceptive response to morphine was reversed by concurrent adminis tration of N-G-nitro-L-arginine (L-NNA) (5 mg/kg, IP), an inhibitor of nitric oxide synthase. 3. The concentrations of morphine in mice trea ted chronically with L-arginine and then given morphine (10 mg/kg, SC) were determined in the peripheral tissues. L-Arginine treatment signi ficantly 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 rever sed the changes induced by chronic treatment with L-arginine. 4. Acute administration of L-arginine (200 mg/kg, IP) did not modify either th e morphine antinociception or the morphine distribution in peripheral tissues.5. Previous studies from this laboratory indicated that chroni c treatment with L-arginine decreases the concentration of morphine in several brain regions and spinal cord of mice. 6. The facts that chro nic treatment with L-arginine does not alter antinociception induced b y ICV administered morphine and it increases the concentration of morp hine in peripheral tissues while decreasing it in brain regions after peripheral administration of morphine suggest that the decreased antin ociception induced by subcutaneously administered morphine may be rela ted to its decreased entry into the brain. (C) 1998 Elsevier Science I nc.