EFFECT OF MORPHINE-TOLERANCE AND ABSTINENCE ON THE BINDING OF [H-3] MK-801 TO BRAIN-REGIONS AND SPINAL-CORD OF THE RAT

The effect of chronic administration of morphine to rats on the N-methyl-D-aspartate (NMDA) receptors labeled with [H-3]MK-801, a non-competitive antagonist, was determined in brain regions and spinal cord. Male Sprague-Dawley rats were rendered tolerant to and physically dependent on morphine by subcutaneous implantation of 6 morphine pellets during a 7-day period. Each pellet contained 75 mg of morphine free base. Animals serving as controls were similarly implanted with placebo pellets. This procedure resulted in the development of a high degree of tolerance and physical dependence on morphine. Two sets of rats were used. In one, the pellets were left intact at the time of sacrifice (tolerant) and in the other the pellets were removed 16 h prior to sacrificing (abstinent). The binding constants, B(max) and K(d) values of [H-3]MK-801 were determined in cortex, hippocampus, hypothalamus, corpus striatum, midbrain and spinal cord. In the absence of glycine and glutamate, [H-3]MK-801 bound to tissue membranes at a single high affinity site. The B(max) and K(d) values of [H-3]MK-801 were not altered in any of the tissues of the morphine abstinent rats. The B(max) value of [H-3]MK-801 was significantly decreased in cerebral cortex of morphine tolerant rats as compared to their placebo controls but the K(d) values did not change. In other brain regions and spinal cord of morphine tolerant rats and their placebo controls, the B(max) and K(d) values of [H-3]MK 801 did not differ. Thus, for the first time these studies demonstrate that in the absence of glutamate and glycine, the [H-3]MK-801 recognition sites are down-regulated selectively in the cerebral cortex of morphine tolerant rats.