Dissociation of mu opioid tolerance from receptor down-regulation in rat spinal cord.

The effect of continuous intrathecal infusions of opioids was studied in rats. Chronic intrathecal infusion of the highly selective mu agonist, [NMPhe3, D-Pro4]morphiceptin produced a rapid onset of tolerance to the drug in the analgesic test. However, membrane prepared from the spinal cords of the rats chronically infused with a low dose of the drug showed no statistically significant change in the number of mu or delta receptor binding sites. In addition, membrane prepared from rats challenged with a single high-dose bolus injection of [NMPhe3, D-Pro4]morphiceptin did not produce alterations in the receptor binding number. If the chronically treated rats were challenged with an acute bolus dose of [NMPhe3, D-Pro4]morphiceptin, there was a significant decrease in the number of binding sites. The reduced binding site number was observed for the mu ligand but not for the delta ligand. A similar decrease of receptor binding can also be achieved by chronic infusion of the drug at high doses. Scatchard plot showed a decrease of maximum mu binding sites in the membranes prepared from the combined chronic infusion-acute injection treated rats. Brain tissue from the same rats showed no change in the number of mu and delta receptor binding sites, indicating that the down-regulation of mu receptors was confined to the spinal cord only. Morphine did not induce receptor down-regulation by acute, chronic or combined treatments. These results suggest that in the rat spinal cord, tolerance can be induced without apparent receptor down-regulation.(ABSTRACT TRUNCATED AT 250 WORDS)