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Tolerance induced by non-opioid analgesic microinjections into rat's periaqueductal gray and nucleus raphe.

Several lines of investigations have shown that the microinjection of non-opioid analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) in the midbrain periaqueductal gray matter (PAG) induces antinociception with some effects of tolerance. Our recent findings also have shown the same effects of tolerance in intraperitoneal (i.p.) injections of analgin (metamizol), ketorolac, and xefocam. Moreover, just recently, we have shown that microinjection of three NSAIDs analgin, ketorolac and xefocam into the central nucleus of amygdala produces tolerance to these drugs and cross-tolerance to morphine. The present study was designed to examine whether together with analgin, microinjection of another type of NSAIDs clodifen, ketorolac and xefocam into the PAG and the nucleus raphe magnus (NRM) leads to the development of tolerance in male rats. The experiments were carried out on experimental and control (with saline) white male rats by the models of tail-flick (TF, to the stimulation of focusing light beam) and hot plate (HP, paw withdrawal) tests. For microinjections of NSAIDs stainless steel guide cannula was implanted into the PAG and NRM by the stereotaxic atlas. Latency increase of these reflexes indicated the degree of antinociception. Analysis of variance with post-hoc Dunnet Multiple Comparison Test were used for statistical evaluations. Our study showed that microinjection of NSAIDs into the PAG produced antinociception as revealed by a latency increase in TF and HP compared to the baseline control with saline microinjected into the same nucleus. However, when these drugs microinjection subsequent testing also took place in the following days the antinociceptive effects progressively diminished so that on the 4th and especially the 5th experimental days the TF and HP latencies were similar to the averaged control baseline for rats that received repeated (5 days) injections of only saline. On the 5th day, one hour after of NSAIDs testing, experimental groups of rats received i.p. injections of mu-opioid antagonist naloxone and we did not reveal significant alterations in TP and HP latencies in non-opioid tolerant rats as well as in control animals. Microinjections of NSAIDs into the NRM also produced antinociception as revealed by a latency increase in TF and HP compared to the baseline control of as in intact rats so with saline microinjected ones into the same nucleus. Subsequent NSAIDs microinjections caused progressively less antinociception, so by day 4 there was no effect, similar to saline microinjections (baseline control) for both the TF and the HP tests, except analgin. The later did not show complete tolerance even on the 5th experimental day. Special control experiments showed that post-treatment with naloxone in RVM diminished NSAID-induced antinociception on the first and second experimental days and impeded the development of tolerance to the antinociceptive effect of NSAIDs. Obtained results underscore the strong convergence of antinociceptive mechanisms of opioids and non-opioids, particularly NSAIDs in the PAG-RVM downstream circuit in the acute effect of and the development of tolerance to both types of analgesics. On the other hand, our data confirm the results of other authors that NSAIDs are in close relation with endogenous opioids and the tolerance to these non-opioid drugs probably depends on opioid tolerance.