Fever and lethargy induced by subcutaneous pyrogen infusion in unrestrained rats

We have investigated the effects of continuous subcutaneous infusion of lipopolysaccharide (LPS), muramyldipeptide (MDP), or saline on abdominal temperature and voluntary activity in unrestrained rats. Both pyrogens were infused via osmotic pumps at a rate of approximately 2 microg.kg-1.min-1 for 7 d. LPS infusion evoked a 3-d and MDP a 1-d elevation in body temperature. Night-time activity was suppressed on days 1 and 2 during LPS infusion and on day 1 of MDP infusion. Body mass was significantly decreased on infusion day 4 in rats receiving either LPS or MDP; however, the rate of weight gain had been restored by day 8 (1 d after cessation of pyrogen infusion). We further tested the body temperature response of the same experimental animals to a single subcutaneous bolus injection (250 microg/kg) of the same pyrogen that had been infused for 7 d, 2 d after cessation of pyrogen infusion (day 9). The fever response in rats receiving a bolus injection of either LPS or MDP was significantly attenuated in rats that had previously been infused with the same pyrogen. These data suggest that tolerance developed to continuous infusion of both Gram-negative and Gram-positive pyrogens, and that mechanisms of tolerance development set in early during the 7-d infusion period of both pyrogens and persisted for at least 2 d after the cessation of pyrogen infusion. We propose that cytokine intermediates were involved or required in inducing these responses to continuous infusion of both LPS and MDP.