Blockade of tolerance to stress-induced analgesia by MK-801 in mice.

The N-methyl-D-aspartate (NMDA) receptor has been implicated in mechanisms of tolerance to morphine-induced analgesia. The present study examined the role of the NMDA receptor in the development of tolerance to stress-induced analgesia (SIA). In the first experiment, mice were exposed to a stressor (a 3-min forced swim in water maintained at 32 degrees C) once daily for 15 consecutive days. Analgesia was measured 2 min after stress on the first and last day using the hot-plate test. To examine the role of the NMDA receptor in the development of tolerance to SIA mice were treated daily with the non-competitive NMDA receptor antagonist, MK-801, 15 min before swimming. Pretreatment with MK-801 was found to block both analgesia and tolerance. In a second experiment, to examine whether SIA and tolerance to SIA are mediated by similar or different mechanisms, mice were injected daily with MK-801 after analgesia had dissipated (1 h following swim). Tolerance to SIA was blocked by delayed injections of MK-801. These results suggest that the NMDA receptor is involved in mechanisms of tolerance to SIA, independent of its role in analgesia.