Antinociceptive tolerance to NSAIDs in the agranular insular cortex is mediated by opioid mechanism

Several lines of investigations have shown that in some brain areas, in particular, in the midbrain periaqueductal gray matter, rostral ventromedial medulla, central nucleus of amygdala, nucleus raphe magnus, and dorsal hippocampus, microinjections of nonsteroidal anti-inflammatory drugs (NSAIDs) induce antinociception with distinct development of tolerance. The agranular insular cortex (AIC) is a small region of the cerebral cortex located on the lateral area of the rat's cerebral hemisphere that is involved in the perception and response to pain. In the present study, we investigated the development of tolerance to the analgesic effects of NSAIDs diclofenac, ketorolac, and xefocam microinjected into the AIC in rats. Male Wistar rats receiving NSAIDs into the AIC were tested for antinociception by tail-flick and hot plate tests. Treatment with each NSAID significantly enhanced the tail-flick and hot plate latencies on the first day, followed by a progressive decrease in the analgesic effect over a 4-day period, ie, they developed tolerance. Pretreatment with an opioid antagonist naloxone completely prevented, and posttreatment naloxone abolished, the analgesic effects of the three NSAIDs in both behavioral assays. These findings support the notion that the development of tolerance to the antinociceptive effects of NSAIDs is mediated via an endogenous opioid system possibly involving descending pain modulatory systems.