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Intrathecal carbachol and clonidine produce a synergistic antiallodynic effect in rats with a nerve ligation injury

L’administration intrathécale de carbachol et de clonidine produit un effet antiallodynique synergique chez des rats présentant une ligature nerveuse

Canadian Journal of Anesthesia volume 49, pages 178–184 (2002)Cite this article

Abstract

Purpose

Antiallodynic effects have been demonstrated after intrathecal administration of α-2 adrenoceptor agonists and cholinesterase inhibitors in rats. Intrathecal carbachol also increases the activity of cholinergic receptor system at the spinal level. However, there is no study regarding the antagonism of carbachol on touch-evoked allodynia and the interaction with clonidine. This study examines the intrathecal interaction between two drugs in a rat model of nerve ligation injury.

Methods

Rats were prepared with tight ligation of the left LS-6 spinal nerves and chronic intrathecal catheter implantation. Tactile allodynia was measured by using application of von Frey filaments to the lesioned hindpaw. Carbachol (0.3–10 μg) and clonidine (1–30 μg) were administered to obtain the dose-response curves and the 50% effective dose (ED50 for each drug. Fractions of ED50 values (1/2, 1/4, 1/8, and 1/16) were administered intrathecally to establish the ED50 of the carbachol-clonidine combination. Isobolographic and fractional analyses of drug interaction were performed.

Results

Intrathecal carbachol and clonidine alone produced a dose-dependent reduction of tactile allodynia without severe motor weakness or sedation. A carbachol-clonidine combination produced a dose-dependent increase in withdrawal threshold of the lesioned hindpaw with a reduced incidence and magnitude of side effects. Both analyses revealed a synergistic interaction after the coadministration of carbachol and clonidine.

Conclusions

This study indicates that carbachol, like clonidine, provides a moderate antagonism on touch-evoked allodynia at the spinal level. The results suggest that intrathecally administered carbachol is synergistic when combined with clonidine.

Résumé

Objectif

Des effets antiallodyniques ont été mis en évidence à la suite de l’administration intrathécale d’agonistes d’ α-2 adrénergique et d’inhibiteurs de la cholinestérase chez des rats. L’administration intrathécale de carbachol augmente aussi l’activité du système récepteur cholinergique au niveau rachidien. Cependant, il n’existe pas d’étude sur l’antagonisme du carbachol sur l’allodynie déclenchée par le toucher, ni sur l’interaction avec la clonidine. La présente étude vérifie l’interaction intrathécale de deux médicaments sur un modèle de lésion par ligature nerveuse chez le rat.

Méthode

Les rats ont été préparés par une ligature serrée des nerfs rachidiens gauches à L5–6 et l’implantation d’un cathéter intrathécal à demeure. L’allodynie tactile a été mesurée par l’application de filaments de von Frey sur la patte arrière lésée. On a administré du carbachol (0,3–10 μg) et de la clonidine (1–30 μg) et obtenu des courbes dose-réponse et la dose efficace 50% (DE50) pour chaque médicament. L’administration de fractions de DE50 (1/2, 1/4, 1/8 et 1/16) par voie intrathécale a permis d’établir la DE50 de la combinaison de carbachol et de clonidine. Des analyses isobolographiques et fractionnelle de l’interaction médicamenteuse ont été réalisées.

Résultats

Le carbachol et la clonidine employés seuls ont produit un réduction de l’allodynie tactile dépendante de la dose sans faiblesse motrice ou sédation importante. Une combinaison des deux médicaments a fait augmenter la valeur seuil du retrait de la patte lésée, en fonction de la dose, et une réduction de l’incidence et de l’importance des effets secondaires. Les deux analyses ont révélé une interaction synergique après la co-administration de carbachol et de clonidine.

Conclusion

Cette étude montre que le carbachol, comme la clonidine, fournit un antagonisme modéré à l’allodynie tactile au niveau rachidien. Les résultats laissent croire à l’action synergique d’une combinaison de carbachol et de clonidine intrathécaux.

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Affiliations

  1. Department of Anaesthesiology, University of Ulsan, College of Medicine, Asan Medical Center, Seoul, Korea

    Eun-Ju Lee, Ji-Yeon Sim, Jong-Yeon Park, Jai-Hyun Hwang, Pyung-Hwan Park & Sung-Min Han

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  1. Eun-Ju Lee
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Correspondence to Jai-Hyun Hwang.

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Lee, EJ., Sim, JY., Park, JY. et al. Intrathecal carbachol and clonidine produce a synergistic antiallodynic effect in rats with a nerve ligation injury. Can J Anesth 49, 178–184 (2002). https://doi.org/10.1007/BF03020492

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Keywords

  • Neuropathic Pain
  • Clonidine
  • Carbachol
  • Spinal Nerve Ligation
  • Tactile Allodynia