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 relati ng morphine dose to tail-flick latencies and provoked hyperalgesic res ponses 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-phosphonopentanoi c acid (AP-5) into the lateral ventricle reversed the hyperalgesic res ponses but spared the tolerance to morphine analgesia. By contrast, sy stemic administration of the noncompetitive NMDA receptor antagonist M K-801 or intrathecal infusion of AP-5 reversed the hyperalgesic respon ses as well as the tolerance to morphine analgesia. The results demons trate that associatively mediated tolerance ro morphine analgesia can co-occur with hyperalgesic responses and are discussed relative to lea rned activation of endogenous pronociceptive mechanisms.