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Delayed application of MK-801 attenuates development of morphine tolerance in rats
P Marek1, S Ben-Eliyahu, A L Vaccarino
1Department of Psychology, University of California, Los Angeles 90024.
Abstract:
To investigate the possible involvement of enduring or delayed changes at the N-methyl-D-aspartic acid (NMDA) receptor in the mechanisms of morphine tolerance, rats were treated with the specific NMDA receptor antagonist, MK-801 (0.15 mg/kg) 2 h after morphine injection (20 mg/kg) during a 4-day induction period of tolerance. On the fifth day rats were injected only with morphine (15 mg/kg), and analgesia was assessed using the hot-plate test. Morphine tolerance was significantly reduced by MK-801. These findings suggest that long-lasting or delayed changes at the NMDA receptor underlie the development of morphine tolerance. Moreover, because MK-801 was delivered 2 h after morphine and therefore could not serve as a cue for morphine administration, these findings indicate that the attenuating effect of MK-801 on the development of morphine tolerance is not attributable to state-dependent learning.
Insights
Blocking N-methyl-D-aspartic acid (NMDA) receptors with MK-801 significantly reduced morphine tolerance in rats. This suggests NMDA receptor changes are key to developing tolerance to morphine analgesia.
Area of Science:
- Neuroscience
- Pharmacology
- Pain Research
Background:
- Morphine tolerance, a decreased response to the drug over time, is a significant clinical challenge.
- The precise mechanisms underlying morphine tolerance are not fully understood.
- N-methyl-D-aspartic acid (NMDA) receptors are implicated in various forms of neuronal plasticity and learning.
Purpose of the Study:
- To investigate the role of NMDA receptor changes in the development of morphine tolerance.
- To determine if antagonism of NMDA receptors can attenuate morphine tolerance.
Main Methods:
- Rats received daily morphine injections for 4 days to induce tolerance.
- The NMDA receptor antagonist MK-801 was administered 2 hours after morphine injections during the induction period.
- Analgesia was assessed using the hot-plate test on the fifth day.
Main Results:
- Administration of MK-801 significantly reduced the development of morphine tolerance.
- The effect was observed even when MK-801 was given after morphine, ruling out state-dependent learning.
Conclusions:
- Enduring or delayed changes at the NMDA receptor are likely involved in the mechanisms of morphine tolerance.
- Targeting NMDA receptors may offer a therapeutic strategy to mitigate morphine tolerance.