Chronically administered morphine increases dopamine receptor sensitivity in mice.

Abstract

Chronic morphine treatment has been suggested to cause the development of supersensitive dopamine receptors. This increase in sensitivity was detected as a hypersensitivity in direct-acting dopamine agonists and as an increase in the affinity of dopamine receptors. However, these binding studies were performed in animals which had been withdrawn from morphine for a period of 24-48 h prior to killing. In the present study mice were implanted with pellets containing 75 mg of morphine free base. The pellets were left in situ in all experiments. One group of mice exhibited an increased sensitivity to apomorphine 72 h following pellet implantation as evidenced by a decrease in the ED50 of apomorphine for inducing cage climbing behavior. A second matched group of mice was found to have a significant increase in whole brain [3H]spiroperidol binding sites. These results suggest that chronic morphine treatment can cause the development of central supersensitive dopamine receptors. Lithium administered concurrently with the morphine attenuated the increased sensitivity to apomorphine and the increase in the number of [3H]spiroperidol binding sites. Concurrent lithium treatment also facilitated the degree of analgesic tolerance, and naloxone-induced withdrawal hypothermia. The ability of lithium to enhance analgesic tolerance while simultaneously attenuating the increase in dopamine receptors suggests that alterations in dopamine receptors might modify the degree of analgesic tolerance which develops to chronic morphine administration, or might modify the animal's response to thermal stimuli. The mechanism by which lithium enhanced naloxone-induced hypothermia is presently unknown.