The NMDA receptor antagonist MK-801 blocks acquisition and extinction of conditioned hypoalgesic responses in the rat.

The role of the N-methyl-D-aspartate (NMDA) receptor in Pavlovian conditioning of hypoalgesic responses in the hotplate apparatus was examined using the non-competitive NMDA antagonist MK-801. Either MK-801 or saline were administered before the training phase, test phase, or both, and MK-801 disrupted the acquisition and extinction but not the expression of conditioned hypoalgesic responses. All rats received counterbalanced injections of both MK-801 and saline after the training phase, therefore the learning decrements could not be attributed to a delayed, non-specific action of the drug. MK-801 did not augment paw-lick latencies on either the training or test days, indicating that its behavioural effects are not due to alterations in nociceptive sensitivity or motor performance. Similarly, MK-801's effects upon acquisition and extinction could not be attributed to state-dependent generalization decrement or impairments in processing of the hot-plate apparatus cues during training, as rats displayed normal hypoalgesic responses when tested with MK-801, and MK-801-treated animals displayed normal habituation of novelty-induced hypoalgesia in the hot-plate apparatus. These data suggest that the NMDA receptor system is involved in the acquisition and extinction, but not the expression of conditioned hypoalgesia and parallels the effects of NMDA receptor antagonists on the acquisition and expression of long-term potentiation (LTP) both in vitro and in vivo. It is plausible that an endogenous NMDA-mediated form of LTP plays a vital role in the acquisition and storage of aversive representations mediating conditioned hypoalgesic responses.