Acute tolerance associated with a single opiate administration: involvement of N-methyl-d-aspartate-dependent pain facilitatory systems
Section snippets
Animals
Experiments were performed on male Sprague–Dawley rats (Iffa–Credo, France), weighing 300–350 g, housed five per cage and maintained under a 12:12-h light/dark cycle (light on at 08.00), with free access to food and water. After arrival in the laboratory, they were allowed a two-weeks rest period before the start of the experiments. Pharmacological tests and care of the animals were in accordance with standard ethical guidelines (NIH, 1985).
Drugs
Diacetyl morphine hydrochloride (heroin) was from
Effect of dizocilpine maleate on naloxone-induced hyperalgesia
As found in a previous study,[11]the administration of naloxone 40 min after heroin injection in the saline-pretreated group not only abolished the analgesia elicited by heroin but also lowered the TF latency below the basal value, revealing hyperalgesia (Fig. 1). One-way ANOVA indicated that pretreatment with MK-801 prevented, in a dose-dependent manner, the hyperalgesia elicited by naloxone (F3,56=11.45, P<0.001). Post-hoc analysis using the Newman–Keuls test revealed that the two higher doses
Discussion
The data presented here suggest that the development of acute tolerance to the analgesic effect of heroin stems from the sustained activation of NMDA-dependent pain facilitatory systems by the first administration of the opiate. The potentiation of the first heroin-induced analgesia in the MK-801-pretreated group of rats also suggests that the development of acute tolerance partly masks the analgesic effect induced by the first heroin injection in normal rats, i.e. those untreated with the NMDA
Conclusions
Taken together, these results suggest that the increased heroin-induced analgesia observed in the MK-801-pretreated rats does not result from a true potentiating effect of the NMDA receptor antagonist, according to the classical definition of potentiation, but rather to the blockade by MK-801 of counteracting systems that systematically oppose the full expression of analgesia induced by opioid receptor stimulation. In other words, the acute tolerance observed in this study did not result from
Acknowledgements
This research was supported by grants from the Fondation pour la Recherche Médicale and the Association pour la Recherche sur le Cancer. A.L. was a recipient of a postdoctoral fellowship from the Société Française de la Douleur and from the Association pour la Recherche sur le Cancer. E.C. is a recipient of a doctoral fellowship from the Ministère de l'Education Nationale, de l'Enseignement Supérieur et de la Recherche.
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