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Antinociceptive synergistic interaction between morphine and nω-nitro 1-arginine methyl ester on thermal nociceptive tests in the rats



This study was conducted to demonstrate if subeffective dose of Nω Nitro L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, interacts with morphine when given intrathecaly (IT), epidurally (EP), and intravenously (IV) to produce a synergistic antinociceptive effect in normal rats.


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°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.


Morphine and L-NAME produced dose-related antinociceptive effects in the IT (ED50 = 1.23 ±0.18 μg (Mean ± SEM) and 76.0 ± 14.5 μg), EP (ED50 = 32.6 + 2.4 μg and 560 ± 97 μg), and IV (ED50 = 563 ± 71.8μ 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 μg in IT, 1.18 ± 0.32 μg in EP, and 50.5 ± 11.4 μg in TV groups) (P < 0.01), suggesting a multiplicative interaction of L-NAME with morphine.


L-NAME has a synergistic antinociceptive interaction with morphine in response to thermal stimulation when given intrathecally, epidurally or intravenously in rats.



Rechercher si le Nω nitro L-arginine méthyl ester (L-NAME), un inhibiteur de la synthétase de l’oxyde nitrique administré à doses réduites avec de la morphine par la voie intrathécale (IT), épidurale (EP) ou intraveinesuse (IV) agissait en synergie avec celle-ci sur l’effet antinociceptif chez le rat normal.


Cette étude a été réalisées chez 72 rats Wistar porteurs de cathéters à demeure. Nous avons utilisé l’épreuve de latence de la déviation de la queue en réponse à la stimulation thermique sur plaque chauffante (53%), et déterminé les caractéristiques dose-effet de la morphine IT, EP et IV, du L-NAME, et de la morphine et des doses réduites de L-NAME administrées conjointement. L’effet antinociceptif était évalué avec la moitié des doses de L-NAME susceptibles de produire 50% de l’effet maximal attendu (ED50). L’interaction entre la morphine et la L-NAME était évaluée par isobolographie. L’ANOVA a servi pour l’analyse statistique. La valeur P < 0,05 était considérée comme significative.


La morphine et L-NAME avaient une activité antinociceptive proportionnelle à la dose dans les groupes IT (ED50 = 1,23 ± 0,18 μg (moyenne ± SEM) et 76 ± 14.5 μg), EP (ED50 = 32,6 ±2,4 μg et 560 ± 97 μg) et IV(ED50 = 563 ±71,8 μg et 16,0 ± 4,0 mg). L’administration conjointe de petites doses de L-NAME et de morphine réduisait les valeurs d’ED50 pour la morphine (0,15 ± 0,03 μg en IT, 1,18 ± 0,32 μg en EP et 50 ± 11,4 μg en IV; P < 0,01) suggérant une interaction multiplicatrice de L-NAME avec morphine.


Le L-NAME posséde une interaction antinociceptive synergique avec la morphine en réponse à la stimulation thermique lorsqu’ils sont administrés conjointement par la voie intrathécale, épidurale ou intraveineuse.


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Correspondence to Hiroshi Yamaguchi.

Additional information

Supported in part by the grants #02770937 (1991) and #03770963 (1992) from the National Agency of Education, Japan.

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Yamaguchi, H., Naito, H. Antinociceptive synergistic interaction between morphine and nω-nitro 1-arginine methyl ester on thermal nociceptive tests in the rats. Can J Anaesth 43, 975 (1996).

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Key words

  • Analgesia: acute pain
  • Analgesics: morphine
  • Anaesthetic Techniques: intrathecal, epidural, intravenous
  • Pharmacodynamics: dose-response, interaction
  • Pharmacology: L-NAME