The NMDA receptor antagonist MK-801 prevents long-lasting non-associative morphine tolerance in the rat

Shamgar Ben-Eliyahu, Przemyslaw Marek, Anthony L. Vaccarino, Jeffrey S. Mogil, Wendy F. Sternberg, John C. Liebeskind*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Several studies have demonstrated that the N-methyl-D-aspartate (NMDA) antagonist MK-801 attenuates the development of morphine tolerance and withdrawal. These studies employed repeated morphine injections to induce tolerance, a procedure in which learning has been suggested to play a significant role in tolerance development. MK-801 has been reported to block some types of learning, and it is unclear, therefore, whether the effect of MK-801 on tolerance development is due to its antagonism of associative (learning) or non-associative factors. Moreover, previous studies have tested the effects of MK-801 on morphine tolerance only up to 48 h after its induction; yet morphine tolerance can persist for many months, and it is not known whether MK-801 can block long-lasting tolerance. In the present study, therefore, we adopted a model of morphine tolerance in which the involvement of learning is minimized by using a single injection of morphine in a sustained-release preparation, and we tested tolerance for up to 56 days. In the first experiment, simultaneously administering MK-801 (0.2 mg/kg, s.c.) and morphine (60 mg/kg, s.c.), each in a sustained-release preparation, abolished tolerance that lasted at least 12 days. Analgesia was measured in the hot-plate test following a test dose of morphine (15 mg/kg, i.p.). In the second experiment, delivering MK-801 and morphine as before, the duration of morphine-induced catalepsy and analgesia was prolonged. Nevertheless, 24 h later one symptom of naloxone-precipitated withdrawal was significantly attenuated in these same animals. These data suggest that NMDA receptors play a crucial role in mediating the development of long-lasting, non-associative morphine tolerance. The prolongation of morphine's analgesic and cataleptic effects by MK-801 suggests further the interesting possibility that some portion of the normally observed decrement in the physiological response to opiates is attributable to the manifestation of acute tolerance, a phenomenon not normally seen until the effects of a second opiate administration are measured, but revealed in the present study by the tolerance-blocking effect of MK-801.

Original languageEnglish
Pages (from-to)304-308
Number of pages5
JournalBrain Research
Issue number2
StatePublished - 20 Mar 1992
Externally publishedYes


FundersFunder number
National Institutes of Health
National Institute of Mental Health
National Institute of Neurological Disorders and StrokeR01NS007628
Bristol-Myers Squibb
Luonnontieteiden ja Tekniikan Tutkimuksen Toimikunta


    • Conditioning
    • Learning
    • MK-801
    • Morphine tolerance
    • N-Methyl-D-aspartate
    • Withdrawal


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