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Dextromethorphan potentiates morphine antinociception at the spinal level in rats

Le dextrométhorphane potentialise l’antinociception de la morphine au niveau rachidien chez les rats

  • Regional Anesthesia and Pain
  • Published:
Canadian Journal of Anesthesia Aims and scope Submit manuscript

Abstract

Purpose

Morphine is an effective analgesic, but adverse effects limit its clinical use in higher doses. The non-opioid antitussive, dextromethorphan (DM), can potentiate the analgesic effect of morphine and decrease the dose of morphine in acute postoperative pain, but the underlying mechanism remains unclear. We previously observed that DM increases the serum concentration of morphine in rats. Therefore, we investigated the effects of drugs administered at the spinal level to exclude possible pharmacokinetic interactions. As DM has widespread binding sites in the central nervous system [such as N-methyl-D-aspartate (NMDA) receptors, sigma receptors and α3ß4 nicotinic receptors], we investigated whether the potentiation of morphine antinociception by DM at the spinal level is related to NMDA receptors.

Methods

We used MK-801 as atool to block the NMDA channel first, and then studied the interaction between intrathecal (i.t.) morphine and DM. The tail-flick test was used to examine the antinociceptive effects of different combinations of morphine and other drugs in rats.

Results

DM (2–20 μg) or MK-801 (5–15 μg) showed no significant antinociceptive effect by themselves. The antinociceptive effect of morphine (0.5 μg, i.t.) was significantly enhanced by DM and reached the maximal potentiation (43.7%–50.4%) at doses of 2 to 10 μg. Pretreatment with MK-801 (5 or 10μg, i.t.) significantly potentiated morphine antinociception by 49.9% or 38.7%, respectively. When rats were pretreated with MK-801, DM could not further enhance morphine antinociception (45.7%vs 50.5% and 43.3%).

Conclusion

Our results suggest that spinal NMDA receptors play an important role in the effect of DM to potentiate morphine antinociception.

Résumé

Objectif

Analgésique efficace, la morphine a cependant des effets indésirables qui en limite l’usage clinique à fortes doses. L’antitussif, dextrométhorphane (DM), peut augmenter l’effet analgésique de la morphine et permettre d’en utiliser une dose postopératoire plus faible, mais le mécanisme responsable de cette action est encore inconnu. Nous savons que le DM augmente la concentration sérique de la morphine chez les rats. Nous avons donc voulu explorer les effets de médicaments administrés au niveau rachidien afin d’exclure des interactions pharmacocinétiques possibles. Les sites de fixation du DM étant nombreux dans le système nerveux central [comme les récepteurs N-méthyl-D-aspartate (NMDA), les récepteurs sigma et les récepteurs nicotiniques α3ß4], nous avons vérifié si la potentialisation de l’antinociception de la morphine par le DM au niveau rachidien est reliée aux récepteurs NMDA.

Méthode

Nous avons utilisé le MK-801 pour bloquer d’abord le canal NMDA et étudier ensuite l’interaction entre la morphine intrathécale (i.t.) et le DM. Le test de latence de rétraction de la queue a été utilisé pour vérifier les effets antinociceptifs de différentes combinaisons de morphine et d’autres médicaments chez les rats.

Résultats

Le DM (2– 20 μg) ou le MK-801 (5– 15 μg) n’ont montré aucun effet antinociceptif significatif par euxmêmes. L’effet antinociceptif de la morphine (0,5 μg, i.t.) a été significativement accru par le DM et a atteint sa potentialisation maximale (43,7 % –50,4 %) aux doses de 2 à 10 μg. Un prétraitement avec MK-801 (5 ou 10 μg, i.t.) a significativement augmenté l’effet antinociceptif de la morphine de 49,9% ou de 38,7 %, respectivement. Chez les rats prétraités avec MK-801, le DM ne pouvait augmenter davantage l’antinociception de la morphine (45,7% vs 50,5% et 43,3%). Conclusion : Nos résultats indiquent que les récepteurs NMDA jouent un rôle important dans l’effet de potentialisation de l’antinociception de la morphine par le DM.

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Authors and Affiliations

  1. Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan

    Lok-Hi Chow

  2. Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan

    Eagle Y. -K. Huang & Pao-Luh Tao

  3. Department of Anesthesiology, National Defense Medical Center, Taipei, Taiwan

    Shung-Tai Ho

  4. Department of Anesthesiology, Tri-Service General Hospital, Taipei, Taiwan

    Shung-Tai Ho

  5. Department of Anesthesiology, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, Taiwan

    Lok-Hi Chow & Tak-Yu Lee

Authors
  1. Lok-Hi Chow
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  2. Eagle Y. -K. Huang
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  3. Shung-Tai Ho
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  4. Tak-Yu Lee
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  5. Pao-Luh Tao
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Corresponding author

Correspondence to Pao-Luh Tao.

Additional information

This study was supported by grants from the National Health Research Institutes (NHRI-EX92-8909BP) and the Taipei Veterans General Hospital (92-V313), Taipei, Taiwan.

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Chow, LH., Huang, E.Y.K., Ho, ST. et al. Dextromethorphan potentiates morphine antinociception at the spinal level in rats. Can J Anesth 51, 905–910 (2004). https://doi.org/10.1007/BF03018888

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  • DOI: https://doi.org/10.1007/BF03018888

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