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INFLAMMATION AND CYTOKINES

Preoptic norepinephrine mediates the febrile response of guinea pigs to lipopolysaccharide

Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee

Submitted 30 January 2007 ; accepted in final form 15 June 2007

Norepinephrine (NE) microdialyzed in the preoptic area (POA) raises core temperature (T_c) via 1) ₁-adrenoceptors (AR), quickly and independently of POA PGE₂, and 2) ₂-AR, after a delay and PGE₂ dependently. Since systemic lipopolysaccharide (LPS) activates the central noradrenergic system, we investigated whether preoptic NE mediates LPS fever. We injected LPS (2 µg/kg iv) in guinea pigs prepared with intra-POA microdialysis probes and determined POA cerebrospinal (CSF) NE levels. We similarly microdialyzed prazosin (₁ blocker, 1 µg/µl), yohimbine (₂ blocker, 1 µg/µl), SC-560 [cyclooxygenase (COX)-1 blocker, 5 µg/µl], acetaminophen (presumptive COX-1v blocker, 5 µg/µl), or MK-0663 (COX-2 blocker, 0.5 µg/µl) in other animals before intravenous LPS and measured CSF PGE₂. All of the agents were perfused at 2 µg/min for 6 h. T_c was monitored constantly. POA NE peaked within 30 min after LPS and then returned to baseline over the next 90 min. T_c increased within 12 min to a first peak at 60 min and to a second at 150 min and then declined over the following 2.5 h. POA PGE₂ followed a concurrent course. Prazosin pretreatment eliminated the first T_c rise but not the second; PGE₂ rose normally. Yohimbine pretreatment did not affect the first T_c rise, which continued unchanged for 6 h; the second rise, however, was absent, and PGE₂ levels did not increase. SC-560 and acetaminophen did not alter the LPS-induced PGE₂ and T_c rises; MK-0663 prevented both the late PGE₂ and T_c rises. These results confirm that POA NE is pivotal in the development of LPS fever.

prostaglandin E₂; cyclooxygenase inhibitors; noradrenergic receptor antagonists; pyrogen signaling; body temperature

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