Antinociceptive tolerance to NSAIDs in the anterior cingulate cortex is mediated via endogenous opioid mechanism.

BACKGROUND: In the past decade several studies have reported that in some brain areas, particularly, in the midbrain periaqueductal gray matter, rostral ventro-medial medulla, central nucleus of amygdala, nucleus raphe magnus, and dorsal hippocampus, microinjections of non-steroidal anti-inflammatory drugs (NSAIDs) induce antinociception with distinct development of tolerance. Given this evidence, in this study we investigated the development of tolerance to the analgesic effects of NSAIDs diclofenac, ketorolac and xefocam microinjected into the rostral part of anterior cingulate cortex (ACC) in rats. METHODS: Male Wistar experimental and control (saline) rats were implanted with a guide cannula in the ACC and tested for antinociception following microinjection of NSAIDs into the ACC in the tail-flick (TF) and hot plate (HP) tests. Repeated measures of analysis of variance with post-hoc Tukey-Kramer multiple comparison tests were used for statistical evaluations. RESULTS: Treatment with each NSAID significantly enhanced the TF and HP latencies on the first day, followed by a progressive decrease in the analgesic effect over a 4-day period, i.e., developed tolerance. Pretreatment with an opioid antagonist naloxone completely prevented the analgesic effects of the three NSAIDs in both behavioral assays. CONCLUSIONS: These findings support the concept that the development of tolerance to the antinociceptive effects of NSAIDs is mediated via an endogenous opioid system possibly involving descending pain modulatory systems.

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.

Antinociceptive tolerance to NSAIDs microinjected into dorsal hippocampus.

BACKGROUND: Pain is characterized as a complex experience, dependent not only on the regulation of nociceptive sensory systems, but also on the activation of mechanisms that control emotional processes in limbic brain areas such as the amygdala and the hippocampus. Several lines of investigations have shown that in some brain areas, particularly the midbrain periaqueductal gray matter, rostral ventro-medial medulla, central nucleus of amygdala and nucleus raphe magnus, microinjections of non-steroidal anti-inflammatory drugs (NSAIDs) induce antinociception with distinct development of tolerance. The present study was designed to examine whether microinjection of NSAIDs, clodifen, ketorolac and xefocam into the dorsal hippocampus (DH) leads to the development of antinociceptive tolerance in male rats. METHODS: The experiments were carried out on experimental and control (with saline) white male rats. Animals were implanted with a guide cannula in the DH and tested for antinociception following microinjection of NSAIDs into the DH in the tail-flick (TF) and hot plate (HP) tests. Repeated measures of analysis of variance with post-hoc Tukey-Kramer multiple comparison tests were used for statistical evaluations. RESULTS: We found that microinjection of these NSAIDs into the DH induces antinociception as revealed by a latency increase in the TF and HP tests compared to controls treated with saline into the DH. Subsequent tests on days 2 and 3, however, showed that the antinociceptive effect of NSAIDs progressively decreased, suggesting tolerance developed to this effect of NSAIDs. Both pretreatment and post-treatment with the opioid antagonist naloxone into the DH significantly reduced the antinociceptive effect of NSAIDs in both pain models. CONCLUSIONS: Our results indicate that microinjection of NSAIDs into the DH induces antinociception which is mediated via the opioid system and exhibits tolerance.