Study of non-opioid analgesics tolerance in young and adult rats.

It was demonstrated that systemic injections of metamizol and lysine-acetylsalicylate (LASA) induce inhibition of tail-flick reflex and hot-plate responses and their repeated administration leads to the development of tolerance. However, it has not been established whether these effects can be elicited by other non-steroidal anti-inflammatory drugs (NSAIDs). In this study the authors used other commonly applied analgesics--analgine, ketorolac, xefocam, which are the representatives of the three diverse groups of NSAIDs. In particular, analgine is a derivative of pirozolon, while ketorolac belongs to indoles and xefocam to amoxicams. The authors decided to examine and compare tolerance to analgine, ketorolac and xefocam in groups of young and adult rats. The experiments were carried out on experimental and control rats with saline by the model of tail-flick reflex to the stimulation of focusing light. Latency increase of this reflex indicates the degree of antinociception. The present study has revealed that systemic, intraperitoneal injections of NSAIDs (analgine, ketorolac and xefocam), the equivalent to maximal analgesic doses for humans, induces antinociception in awake rats of young and adult ages and when administered repeatedly, induce tolerance to these drugs and cross-tolerance to morphine. This is in line with results of earlier experiments, in which metamizol or LASA were given intravenously or microinjected into the periaqueductal gray matter. More importantly, the study indicate that the repeated administration of these non-opioid analgesics induces a decrease in antinociceptive effectiveness reminiscent of that induced by opiates. Moreover, the present results paradoxically suggest that analgine, ketorolac and xefocam tolerance is related to the endogenous opioid system. Taken together the present and previous findings the authors support the notion that the contribution of the CNS, particularly of the downstream pain-control system, to the tolerance effects of NSAIDs involve endogenous opioidergic mechanisms.