Thesis

An exploration of the role of N-methyl-D-aspartate receptors in opiate tolerance, sensitization, and physical dependence

When opiates are used chronically changes in their effects occur. These changes include tolerance, sensitization and physical dependence. Tolerance is a decrease in effect after chronic administration, sensitization is an increase in effect after chronic administration and physical dependence is altered physiological activity in the absence of the drug. Previous research has shown that N-methyl-D-aspartate (NMDA) receptor antagonists can modify these phenomena. However, many of these studies focused on specific behavioral effects such as analgesia. It is of interest to explore the role ofNMDA receptors in other behaviors in which tolerance, sensitization and physical dependence are seen to occur. In four experiments the role ofNMDA receptors in the development of tolerance, sensitization and physical dependence to the locomotor effects of morphine were explored. Using an NMDA receptor antagonist, MK-801, in combination with morphine, the locomotor behavior of Sprague-Dawley rats was analyzed. The first experiment was designed to develop a sensitive procedure in which the development of tolerance, sensitization and physical dependence to the locomotor effects of morphine could be seen. When morphine is administered acutely there is a typical biphasic pattern of activity, including an initial depression of activity followed by a delayed facilitation of activity. When morphine is administered chronically there is a decrease in the initial depressant effect, or tolerance and an increase in the delayed facilitative effect, or sensitization. In the first experiment animals that had received morphine once daily for 10 days displayed less morphine-induced locomotor depression, indicating the development of tolerance and more morphine-induced locomotor facilitation, indicating the development of sensitization. Further, animals that were previously exposed to morphine but had morphine withheld on the day of testing displayed a decrease in activity indicating the presence of physical dependence. The second experiment examined the acute interaction between MK -801 and morphine in order to determine a dose ofMK-801 to use in subsequent chronic studies. MK-801 by itself (0.05 or 0.10 mg/kg) produced a very mild and short-lived increase in locomotion. Both doses decreased the morphine-induced locomotor depression and increased the morphine-induced locomotor facilitation. Since both doses influenced the effects of morphine in the same way the moderate dose ofMK-801 (.10 mg/kg) was used in the subsequent chronic studies. The third experiment was designed to explore the role of NMDA receptors in the development oftolerance to the analgesic effect of morphine and the development of tolerance and sensitization to the locomotor effects of morphine. Animals were treated once daily for 10 days with saline+ saline, MK-801 +saline, saline+ morphine, or MK-801 +morphine, and tested for the presence of tolerance and sensitization on day 11. The results from the analgesia testing confirm previous research showing that MK-801 inhibits the development of tolerance to the analgesic effect of morphine. The results for locomotor activity reveals the group that received MK-801 in combination with morphine displayed activity similar to that of acute morphine. These data are consistent with the idea that MK-801 does inhibit the development of tolerance to the locomotor depressant effect of morphine and sensitization to the locomotor stimulant effect of morphine. The final experiment was designed to explore the role ofNMDA receptors in the development of physical dependence. A treatment protocol similar to Experiment 3 was used; animals were tested for the presence of physical dependence on day 11. The results show that animals that had received morphine chronically, either alone or in combination with MK -801, displayed signs of withdrawal, indicating the development of physical dependence. However, there was no evidence that MK-801 inhibited the development of physical dependence as the MK-801/morphine combination animals displayed activity similar to that of chronic morphine animals. Overall, the results point to a role for NMDA receptors in the development of tolerance to the analgesic effects of morphine, and tolerance and sensitization to the locomotor stimulant effects. Further research will help to clarify the specific role that NMDA receptors have in opiate tolerance, sensitization and physical dependence.

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