Douleur et Analgésie

, 14:219 | Cite as

Analgésiques opiacés et hyperalgésie implications thérapeutiques

  • G. Simonnet
  • E. Célèrier


Il est bien admis que certaines lésions tissulaires peuvent induire de longues hyperalgésies, allodynies voire des douleurs spontanées. Bien que les substances opiacées soient de puissants analgésiques, nous avons pu observer qu’ils peuvent également activer des systèmes facilitateurs de la nociception (systèmes pronociceptifs) qui s’opposent dès la première administration aux effets analgésiques des substances opiacées et peuvent conduire à des hyperalgésies de longue durée. Les antagonistes des récepteurs NMDA, tels que le MK-801 ou la kétamine, peuvent prévenir totalement ces phénomènes et amplifier l’effet analgésique opiacé. Nous avons pu également observer que l’administration répétée d’une substance opiacée entraîne une augmentation de la sensibilité à la douleur qui masque de plus en plus un effet analgésique qui apparaît invariant donnant l’impression d’une tolérance aux effets analgésiques. Ce phénomène de sensibilisation à la douleur peut également être prévenu par les antagonistes NMDA. La capacité de la naloxone à induire une hyperalgésie chez les animaux qui ont retrouvé progressivement un seuil nociceptif normal après sevrage suggère que les animaux préalablement traités par la substance opiacée ne sont pas revenus à leur état initial mais sont dans un nouvel état correspondant à un nouvel équilibre à haut niveau entre systèmes analgésiques opioïde-dépendants et des systèmes pronociceptifs NMDA-dépendants. L’ensemble de ces données suggère que tolérance et sensibilisation à la douleur relèvent d’un même continuum adaptatif dans lequel les systèmes glutamatergiques NMDA-dépendants pourraient jouer un rôle majeur. Le rôle possible d’un tel processus dans le phénomène de chronicisation de la douleur est discuté.


Analgésiques opiacés hyperalgésie tolérance douleur chronique 


It is generally acknowledged that damage to tissue may produce persistent hyperalgesia, allodynia or spontaneous pain. Besides the analgesic effects of opiates, we report here a series of observations showing that various opiates acting upon μ opioid receptors may simultaneously activate pronociceptive systems that oppose the full expression of analgesia and lead to long-lasting hyperalgesia (days). NMDA receptor antagonists, such as MK-801 or ketamine, prevent these phenomena and enhance the analgesic effect of opiates suggesting that the latter is systematically blunted by concomitant NMDA-dependent opposing effects. Moreover, we observed that repeated injections of an opiate induce a gradual enhancement of pain sensitivity which progressively masks a sustained opiate analgesic effect. NMDA receptor antagonists also prevent such an opiate-induced hyperalgesia and thereby prevent an apparent decrease in the effectiveness of the opiate. These results suggest that intermittent opiate administration induces a pain sensitization process which, if not taken into account gives the impression of less analgesia, i.e. apparent tolerance. The effectiveness of the opioid receptor antagonist naloxone to precipitate hyperalgesia in rats which had recovered their pre-drug nociceptive threshold after a series of repeated opiate administrations, indicates that opiate-treated animals are in a new biological state associated with a high level balance of opioid-dependent analgesic systems and NMDA-dependent pronociceptive systems. These findings further suggest that tolerance and pain sensitization issue from a neuroadaptivecontinum in which NMDA receptors play a critical role. Whether this adaptive process is involved in mechanisms leading to chronic pain is discussed.


Opiate analgesic hyperalgesia tolerance chronic pain 


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Copyright information

© Springer-Verlag 2001

Authors and Affiliations

  • G. Simonnet
    • 1
  • E. Célèrier
    • 1
  1. 1.INSERM U259Centre François MagendieBordeaux Cedex

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