Characteristics of thermoregulatory and febrile responses in mice deficient in prostaglandin EP₁ and EP₃ receptors

Previous studies have disagreed about whether prostaglandin EP₁ or EP₃ receptors are critical for producing febrile responses. We therefore injected lipopolysaccharide (LPS) at a variety doses (1 μg kg^-1-1 mg kg^-1) intraperitoneally (I.P.) into wild-type (WT) mice and mice lacking the EP₁ or the EP₃ receptors and measured changes in core temperature (T_c) by using telemetry. In WT mice, I.P. injection of LPS at 10 μg kg^-1 increased T_c. about 1°C, peaking 2 h after injection. At 100 μg kg^-1, LPS increased T_c, peaking 5-8 h after injection. LPS at 1 mg kg^-1 decreased T_c, reaching a nadir at 5-8 h after injection. In EP₁, receptor knockout (KO) mice injected with 10 μg kg^-1 LPS, only the initial (< 40 min) increase in T_c was lacking; with 100 μg kg^-1 LPS the mice showed no febrile response. In EP₃ receptor KO mice, LPS decreased T_c in a dose- and time-dependent manner. Furthermore, in EP₃ receptor KO mice subcutaneous injection of turpentine did not induce fever. Both EP₁ and EP₃ receptor KO mice showed a normal circadian cycle of T_c and brief hyperthermia following psychological stress (cage-exchange stress and buddy-removal stress). The present study suggests that both the EP₁ and the EP₃ receptors play a role in fever induced by systemic inflammation but neither EP receptor is involved in the circadian rise in T_c or psychological stress-induced hyperthermia in mice.