It has recently been shown that antinociceptive tolerance develops by repeated systemic administration of non-steroidal anti-inflammatory drugs (NSAIDs) metamizol and lysine-acetylsalicylate. This is similar to the tolerance observed with opioid-induced analgesia [Vanegas and Tortorici, 2002, Cell and Mol. Neurobiol. 22, 655-661]. In the present study, we investigated the development of tolerance to the analgesic effects of the additional NSAIDs analgine, ketorolac and xefocam in juvenile and adult rats. After injection of each drug, tail-flick latencies were significantly elevated on the first day followed by a progressive decrease in tail-flick latency (i.e., tolerance) over the 5-day period, as well as cross-tolerance to morphine-induced analgesia. Tolerance to the analgesic effect of all three NSAIDs developed more rapidly in juvenile compared to adult rats. Pretreatment with naloxone completely prevented the analgesic effects of these drugs in tail-flick and hot plate tests for both juvenile and adult rats. Moreover, each NSAID exhibited cross-tolerance when tolerance to morphine had been induced by systemic morphine delivered repeatedly over 5-day period in both age groups. Our data confirm other recent findings that tolerance to the analgesic action of NSAIDs may depend on an opiate-mediated mechanism.
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