Fever Response In Rats Research Articles

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.

Effects of selective cyclooxygenase enzyme inhibitors on lipopolysaccharide-induced dual thermoregulatory changes in rats

The effects of selective cyclooxygenase-1 and cyclooxygenase-2 inhibitors (valeryl salicylate and SC-58236, respectively) on Escherichia coli O111:B4 lipopolysaccharide (LPS)-induced dual thermoregulatory changes and serum tumor necrosis factor-α elevation were investigated in rats. LPS (50 μg/kg, intraperitoneal) produced an initial hypothermia that was then followed by fever. Serum tumor necrosis factor-α levels elevated at the initial phase of hypothermia. Valeryl salicylate injections (20, 40, and 80 mg/kg, subcutaneous [s.c.]) completely inhibited hypothermia without any effect on the elevated serum tumor necrosis factor-α levels and on the subsequent fever. On the other hand, SC-58236 injections (10, 20, and 40 mg/kg, s.c.) only partially abolished the hypothermia. SC-58236 had no effect on the initiation of fever, however completely inhibited the maintenance of fever. The serum tumor necrosis factor-α elevation was not reduced by SC-58236 treatment. The combination of valeryl salicylate and SC-58236 also failed to inhibit the initiation of fever. These findings suggest that cycloxygenase-1 may have a predominant role for the development of LPS-induced hypothermia, but cyclooxygenase-1 does not seem to be involved in the mediation of LPS-induced fever. Meanwhile, cyclooxgenase-2 may be critical for the late phase rather than the initiation of the fever response in rats.

Antagonism of central glucagon-like peptide-1 receptors enhances lipopolysaccharide-induced fever

Lipopolysaccharide (LPS; a model of systemic bacterial infection) causes fever and activates glucagon-like peptide-1 (GLP-1) neurons in the caudal brainstem. The present study examined whether central GLP-1 receptor signaling plays a functional role in LPS-induced fever. Adult male Sprague–Dawley rats were injected i.p. with LPS (0 or 100 μg/kg), then were infused intracerebroventricularly with GLP-1 receptor antagonist (0 or 10 μg) delivered 2.5 h after injection of LPS or vehicle. Core body temperature was measured at 30-min intervals for 6.5 h after LPS treatment. Consistent with previous reports, body temperature was significantly elevated within 90 min and remained elevated for the remainder of the monitoring period. The pyrogenic effect of LPS was amplified in rats that received central infusion of GLP-1 receptor antagonist, although the antagonist by itself did not alter body temperature. These findings suggest that endogenous GLP-1 acts at central receptors to limit the fever response in rats after i.p. administration of LPS.

The Effects of Lipopolysaccharide (LPS) on the Fever Response in Rats at Different Ambient Temperatures

CONRAD, A., D. F. BULL, M. G. KING AND A. J. HUSBAND. The effects of lipopolysacchride (LPS) on fever response in rats at different ambient temperatures. PHYSIOL BEHAV 62(6) 1197–1201, 1997.—There is a complex interplay between the immune system, nervous system, and sleep. When an organism is challenged with lipopolysacchride (LPS), the immune system is stimulated, producing a fever response that is independent of ambient temperature, and an increase in slow-wave sleep (SWS). The study investigated sleep patterns of immune-challenged rats during the light phase cycle to determine the effects of various ambient temperatures. It was hypothesised that fever response would occur independently of ambient temperatures. Also, the febrile response would be monophasic, and there would be an increase in slow-wave sleep (SWS) and a decrease in rapid-eye-movement (REM) sleep. Thirty Wistar rats were randomly placed in 3 different ambient temperature groups, 22°C, 15°C, and 30°C. Within each of these conditions, the same subjects served as control and experimental groups. Four animals were placed in 4 subsections of 2 standard boxes that were placed in the ambient-temperature box. The electrodes were connected to the analog to digital computer board, where all the data was processed and stored on a hard drive. The animals were injected IP with saline and recorded for a period of 6 h to establish a baseline. On Day 2, the same animals were injected IP with LPS and recorded for 6 h to determine the febrile effects of LPS on the immune system; the same procedure was repeated in the other ambient temperatures. The results have shown that animals experienced a monophasic fever response in low and normal temperatures, but not in the high temperatures. Although there was no increase in SWS, there was a significant decrease in REM sleep in 3 groups.

Rat endogenous pyrogen and fever.

Rat endogenous pyrogen (EP), prepared from the white blood cells of lipopolysaccharide-pretreated rats, produced a fever in both rabbits and rats. The effects of human, rabbit, and rat EP on the body temperatures of rabbits and rats were investigated to clarify differences in the febrile response to each kind of EP. The latency to fever onset and the time to peak fever induced by rat EP in rabbits and rats were significantly greater than those induced by human and rabbit EP. The maximum elevation of the body temperature induced by rat EP in both animals was almost identical to that induced by human and rabbit EP. In a comparison of the febrile responses to various EPs between rabbits and rats, the latency to fever onset, the time to peak, and the maximum elevation of fever in rats were approximately half those observed for rabbits. Furthermore, the threshold dosage to induce a fever response in rats was greater than that necessary for rabbits. It is concluded that rat EP could be obtained by in vitro techniques and that rats have the physiological mechanisms to develop a fever through production of EP.