The glycine site-specific NMDA antagonist (+)-HA966 enhances the effect of morphine and reverses morphine tolerance via a spinal mechanism.
Using the C-fibre reflex as a nociceptive response elicited by a wide range of stimulus intensities in the rat, we recently reported that a single treatment with (+)-HA966, a glycine site-specific NMDA receptor antagonist: (1) potentiates morphine antinociception; and (2) reverses an established morphine tolerance. We presently aimed at determining whether our observation was likely to result from a direct effect on the spinal cord or an indirect effect of supraspinal origin. In a 2x2x2 experimental design, we compared the effects of 5 mg/kg morphine in: (1) sham-operated rats or animals whose brainstems had been transected at the level of the obex; (2) rats that were implanted with pellets, either 150 mg morphine or placebo; and (3) animals injected either with saline or 10 mg/kg (+)-HA966. The control C-fibre reflexes were similar in all groups of animals. As compared to "non-tolerant" rats, the depressive effect of morphine was weaker in "morphine-tolerant" animals where the threshold did not change following morphine but the gain of the stimulus-response curve decreased, albeit to a significantly lesser extent than in the "non-tolerant" group. Whether in "non-tolerant" or "tolerant" groups, the effects of morphine were stronger in "obex-transected" than in "sham-operated" animals. In all groups, the effects of morphine were potentiated by the preliminary administration of (+)-HA966. However, in the "morphine-tolerant" group, the preliminary administration of (+)-HA966 was more potent in the "sham-operated" than in the "obex-transected" groups. Since overall effects were very similar in "sham-operated" and "obex-transected" animals, we concluded for our model that the critical site for the expression of the neuronal plastic changes associated with morphine tolerance lies in the spinal cord.
Adam
Frédéric
F
Institut National de la Santé et de la Recherche Médicale (INSERM) U-713, Université Pierre et Marie Curie, Faculté de Médecine Pitié-Salpêtrière, 91 Boulevard de l'Hôpital, 75013 Paris, France.
Dufour
Eric
E
Le Bars
Daniel
D
D000818:Animals; D004307:Dose-Response Relationship, Radiation; D004361:Drug Tolerance / Q000502:physiology*; D004558:Electric Stimulation / Q000379:methods; D004576:Electromyography / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D008297:Male; D009020:Morphine / Q000009:adverse effects*; D009021:Morphine Dependence / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D036421:Nerve Fibers, Unmyelinated / Q000502:physiology / Q000528:radiation effects; D010147:Pain Measurement; D011760:Pyrrolidinones / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012018:Reflex / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects* / Q000502:physiology; D013119:Spinal Cord Injuries / Q000503:physiopathology
D018691:Excitatory Amino Acid Antagonists; D011760:Pyrrolidinones; D009020:Morphine; C001369:1-hydroxy-3-amino-2-pyrrolidone