Antinociceptive tolerance to non-steroidal anti-inflammatory drugs microinjected into dorsal hippocampus of rats is due to pharmacological tolerance.

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. We have recently found that repeated microinjection of non-steroidal anti-inflammatory drugs (NSAIDs) into the dorsal hippocampus of rats for four consecutive days induces antinociceptive tolerance as revealed by a progressive decrease of the latency in the tail-flick and hot plate tests compared to controls treated with saline into the dorsal hippocampus. Here we found that on the first day microinjection of NSAIDs, ketorolac, clodifen and xefocam into the DH produced antinociception as revealed by a latency increase in the TF and HP compared to the baseline control of intact rats and a control group with saline microinjected into the same site as well. Subsequent NSAIDs microinjections, without testing on the second and third days, caused progressively less antinociception, i.e. developed tolerance. After two days resting, by day 7 antinociception was almost completely restored for all the three drugs. Thus we demonstrated that this antinociceptive tolerance is due to pharmacological tolerance to these drugs and not to conditioning by repeating testing or hyperalgesia or other nonspecific mechanisms.