Antinociceptive synergistic interaction between morphine and n omega-nitro 1-arginine methyl ester on thermal nociceptive tests in the rats.
OBJECTIVE
This study was conducted to demonstrate if subeffective dose of N omega Nitro L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, interacts with morphine when given intrathecally (IT), epidurally (EP), and intravenously (IV) to produce a synergistic antinociceptive effect in normal rats.


METHODS
Chronically catheterized 72 male Wistar rats were used in this study. We measured the tail flick latency in response to thermal stimulation of the tail on a hot plate (53 degrees C), and determined dose-response functions of IT, EP and IV morphine, L-NAME, and morphine co-administered with subeffective doses of L-NAME. The antinociceptive effect was evaluated using the doses for 50% maximum probable effect (ED50). The interaction between morphine and L-NAME was evaluated using an isobolographic approach. ANOVA was used for the statistical analysis. Significance was taken at P < 0.05.


RESULTS
Morphine and L-NAME produced dose-related antinociceptive effects in the IT (ED50 = 1.23 +/- 0.18 micrograms (Mean +/- SEM) and 76.0 +/- 14.5 micrograms), EP (ED50 = 32.6 +/- 2.4 micrograms and 560 +/- 97 micrograms), and IV (ED50 = 563 +/- 71.8 micrograms and 16.0 +/- 4.0 mg) groups, respectively. Co-administration of small doses of L-NAME and morphine produced reductions in the ED50 values for morphine (0.16 +/- 0.03 microgram in IT, 1.18 +/- 0.32 micrograms in EP, and 50.5 +/- 11.4 micrograms in IV groups) (P < 0.01), suggesting a multiplicative interaction of L-NAME with morphine.


CONCLUSIONS
L-NAME has a synergistic antinociceptive interaction with morphine in response to thermal stimulation when given intrathecally, epidurally or intravenously in rats.
Yamaguchi
H
H
Department of Anesthesiology, University of Tsukuba, Ibaraki, Japan. hyanchi@igaku.md.tsukuba.ac.jp
Naito
H
H
D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D008297:Male; D009020:Morphine / Q000008:administration & dosage*; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010146:Pain / Q000188:drug therapy*; D051381:Rats; D017208:Rats, Wistar
D000701:Analgesics, Opioid; D004791:Enzyme Inhibitors; D009020:Morphine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester