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Blockade of morphine-induced analgesia and tolerance in mice by MK-801
K Lutfy1, D E Hurlbut, E Weber
1Department of Pharmacology, School of Medicine, UC, Irvine 92717.
Abstract:
The effect of MK-801 on morphine-induced analgesia, tolerance and opioid binding sites was examined in mice. In analgesia studies, mice received either naloxone or MK-801. Controls were injected with saline. Mice were then injected with morphine 10 or 30 min following naloxone or MK-801, respectively, and tested for analgesia (tail flick assay) 45 min later. Pretreatment with naloxone or MK-801 blocked morphine-induced analgesia. In tolerance studies, mice were pretreated with either saline or MK-801. Thirty minutes later, mice were injected with either saline or morphine (acutely or chronically) and tested for analgesia 24 h later. Pretreatment with MK-801 partially or completely blocked the development of acute and chronic tolerance, respectively. In binding studies, MK-801 displaced [3H]naloxone poorly compared to naloxone or morphine. Together, these data suggest a role for NMDA receptors in morphine-induced analgesia and tolerance. The poor inhibition of the [3H]naloxone binding sites by MK-801 supports the possibility that MK-801 might not act directly on the opioid receptors, but rather, inhibits morphine-induced analgesia and tolerance by some other mechanisms.
Insights
MK-801, an NMDA receptor antagonist, blocks morphine-induced analgesia and tolerance in mice. This suggests NMDA receptors play a role in opioid effects, independent of direct opioid receptor binding.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Opioid analgesics like morphine are widely used for pain management.
- The development of tolerance to morphine limits its long-term efficacy.
- The precise mechanisms underlying morphine-induced analgesia and tolerance are not fully understood.
Purpose of the Study:
- To investigate the role of N-methyl-D-aspartate (NMDA) receptors in morphine-induced analgesia and tolerance.
- To determine if MK-801, a non-competitive NMDA receptor antagonist, affects morphine's analgesic properties and the development of tolerance.
Main Methods:
- Mice were pretreated with MK-801 or saline before receiving morphine.
- Analgesia was assessed using the tail flick assay.
- Tolerance was evaluated after acute and chronic morphine administration.
- Opioid binding sites were examined using radioligand displacement assays with [3H]naloxone.
Main Results:
- Pretreatment with MK-801 significantly blocked morphine-induced analgesia.
- MK-801 partially or completely inhibited the development of acute and chronic morphine tolerance, respectively.
- MK-801 showed poor displacement of [3H]naloxone from opioid binding sites.
Conclusions:
- NMDA receptors are implicated in morphine-induced analgesia and the development of tolerance.
- MK-801 appears to modulate opioid effects through mechanisms independent of direct interaction with opioid receptors.
- These findings highlight NMDA receptor antagonists as potential adjuncts for enhancing opioid efficacy and managing tolerance.