Mechanism of attenuation of morphine antinociception by chronic treatment with L-arginine.
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 mu-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 Bmax or Kd 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.
Bhargava
H N
HN
Department of Pharmaceutics and Pharmacodynamics, University of Illinois at Chicago Health Sciences Center, USA.
Bian
J T
JT
Kumar
S
S
D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000378:metabolism; D008297:Male; D051379:Mice; D009020:Morphine / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011957:Receptors, Opioid / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D014018:Tissue Distribution; D014316:Tritium
D000701:Analgesics, Opioid; D004745:Enkephalins; D011957:Receptors, Opioid; D014316:Tritium; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009020:Morphine; D001120:Arginine; D019001:Nitric Oxide Synthase