Complete prevention but stimulus-dependent reversion of morphine toleranceby the glycine/NMDA receptor antagonist (+)-HA966 in neuropathic rats

Background: Tolerance to the analgesic effect of morphine complicates the m anagement of chronic pain states. The authors studied the ability of the gl ycine/N-methyl-D-aspartate: receptor antagonist (+)-HA966 to modify morphin e tolerance in a rat model of neuropathic pain, Methods: Mononeuropathy was induced by placing four ligatures around the co mmon sciatic nerve, The 4-day pretreatment regimens with tno daily subcutan eous injections of saline and saline, saline and morphine (10 mg/kg), (+)-H A966 (2.5 mg/kg) and morphine, or (+)-HA966 and saline were begun on postop erative day 12 to test the ability of (+)-HA966 to prevent the development of tolerance. Behavioral experiments were performed on postoperative day 16 , when the pain-related behavior reached a stable maximum. The effect of an acute dose of morphine (1 mg/kg intravenously) was tested against both mec hanical (vocalization threshold to paw pressure) and thermal (struggle late ncy to hind paw immersion into a 46 degrees C hot-water bath) stimuli. In a ddition, to test the ability of a single injection of (+)-HA966 to reverse established morphine tolerance. groups of morphine-pretreated rats received injections of either (+)-HA966 (2.5 mg/kg subcutaneously) and morphine (1 mg/kg intravenously), saline and morphine, or (+)-HA966 and saline. Results: Baseline vocalization thresholds and struggle latencies did not di ffer in the various pretreatment groups, indicating that the pretreatments had no effect on pain-related behavior. Coadministration of (+)-HA966 preve nted the reduction of the effect observed with morphine alone in both the m echanical test and the thermal test. (+)-HA966 reversed morphine tolerance in the thermal but not in the mechanical test. Conclusion: (+)-HA966 prevented morphine tolerance in both mechanical and t hermal tests but re-versed established morphine tolerance in the thermal te st only.