Is hippocampus susceptible to antinociceptive tolerance to NSAIDs like the periaqueductal grey?

Emotional distress is the most undesirable feature of painful experience. Numerous studies have demonstrated the important role of the limbic system in the affective-motivational component of pain. The purpose of this paper was to examine whether microinjection of nonsteroidal anti-inflammatory drugs (NSAIDs), Clodifen, Ketorolac, and Xefocam, into the dorsal hippocampus (DH) leads to the development of antinociceptive tolerance in male rats. We found that microinjection of these NSAIDs into the DH induces antinociception as revealed by a latency increase in the tail-flick (TF) and hot plate (HP) tests compared to controls treated with saline into the DH. Subsequent tests on consecutive three days, however, showed that the antinociceptive effect of NSAIDs progressively decreased, suggesting tolerance developed to this effect of NSAIDs. Both pretreatment and posttreatment with the opioid antagonist naloxone into the DH significantly reduced the antinociceptive effect of NSAIDs in both pain models. Our data indicate that microinjection of NSAIDs into the DH induces antinociception which is mediated via the opioid system and exhibits tolerance.