Tolerance develops to the effect of lipopolysaccharides on movement-evoked hyperalgesia when administered chronically by a systemic but not an intrathecal route.

Single exposures to lipopolysaccharides (LPS) produce deep tissue pain in humans and cutaneous hyperalgesia in rodents. While tolerance develops to many effects of LPS, sensitization to hyperalgesia is documented after a single injection. To determine the effect of long-term exposure to LPS, we explored the chronic effect of LPS on movement-evoked pain using a new assay based on grip force in mice. We found that a single systemic injection of LPS (i.p. or s.c.) induced a dose-related decrease in forelimb grip force responses beginning 6-8 h after injection and peaking between 9 and 24 h. The consequence of LPS is likely hyperalgesia rather than weakness as these decreases were rapidly attenuated by either 10 mg/kg of morphine i.p. or 10 microg of morphine injected intrathecally (i.t.). Complete tolerance to this hyperalgesia developed after repeated injections of LPS at doses of 0.9 mg/kg i.p. or 5 mg/kg s.c. Tolerance began after a single injection and was fully developed after as few as four injections of 5 mg/kg of LPS delivered s.c. The concentration of circulating LPS 5 h after a single parenteral injection was less in LPS-tolerant mice than naïve controls, suggesting that tolerance may result from a more efficient clearance of LPS from the circulation. Injected i.t., LPS also induced hyperalgesia, however, tolerance did not develop to multiple injections by this route. There was no cross-tolerance between s.c. and i.t. injections of LPS. These data indicate that decreases in grip force are a sensitive measure of LPS-induced movement-evoked hyperalgesia and that tolerance develops to parenteral but not central hyperalgesic effects of LPS.