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.