Effects of systemic, intracerebral, or intrathecal administration of an N-methyl-D-aspartate receptor antagonist on associative morphine analgesic tolerance and hyperalgesia in rats.

A flavor paired with morphine shifted to the right the function relating morphine dose to tail-flick latencies and provoked hyperalgesic responses when rats were tested in the absence of morphine. These learned increases in nociceptive sensitivity were not mediated by alterations in tail-skin temperature. Microinjection of the competitive N-methyl-D-aspartate (NMDA) receptor antagonist D,L-2-amino-5-phosphonopentanoic acid (AP-5) into the lateral ventricle reversed the hyperalgesic responses but spared the tolerance to morphine analgesia. By contrast, systemic administration of the noncompetitive NMDA receptor antagonist MK-801 or intrathecal infusion of AP-5 reversed the hyperalgesic responses as well as the tolerance to morphine analgesia. The results demonstrate that associatively mediated tolerance to morphine analgesia can co-occur with hyperalgesic responses and are discussed relative to learned activation of endogenous pronociceptive mechanisms.