EFFECTS OF NMDA RECEPTOR-CHANNEL BLOCKERS, DIZOCILPINE AND MEMANTINE,ON THE DEVELOPMENT OF OPIATE ANALGESIC TOLERANCE INDUCED BY REPEATED MORPHINE EXPOSURES OR SOCIAL DEFEATS IN MICE

Development of tolerance to opiates involves various neurochemically a nd pharmacologically distinct processes. For instance, the diversity o f opiate tolerance has been suggested by experiments comparing the est ablishment of diminished response to different effects of opiate agoni sts. Antagonists acting at N-methyl-D-aspartate (NMDA) receptors has b ecome a very useful tool for studying opiate tolerance mechanisms sinc e these drugs have been shown to retard the development of tolerance t o analgesic properties of opiates. The present study compared the abil ity of two NMDA receptor channel blockers, dizocilpine and memantine, to affect the development of tolerance to morphine analgesia induced b y repeated social defeat or by repeated morphine administrations. Male BALB/c mice were assessed for the tail-flick response before and afte r the defeat in five social confrontations, or before and after repeat ed morphine injections (20 mg/kg, s.c., once daily for 8 days). Repeal ed morphine injections were explicitly paired with environmental cues. Socially-defeated as well as morphine-treated mice developed signific ant tolerance to morphine analgesia. Separate groups of mice were expo sed to repeated social confrontations or injections of morphine with e ach defeat or morphine injection followed by administration of either dizocilpine (0.03-0.3 mg/kg, i.p,) or low-affinity channel blocker mem antine (3-30 mg/kg, i.p.). Both dizocilpine and memantine were effecti ve in preventing the development of repealed morphine-induced toleranc e to acute morphine analgesia. Treatments with NMDA receptor antagonis ts that retarded development of non-associative tolerance also suppres sed the establishment of associative tolerance significantly, Social d efeat-induced tolerance was prevented by dizocilpine but not by memant ine. Our results suggest some degree of similarity in the mechanisms o f morphine analgesic tolerance induced by pharmacological, contextual and social stimuli.